WO2023081209A1 - Pi3k inhibitors and methods of treating cancer - Google Patents
Pi3k inhibitors and methods of treating cancer Download PDFInfo
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- WO2023081209A1 WO2023081209A1 PCT/US2022/048700 US2022048700W WO2023081209A1 WO 2023081209 A1 WO2023081209 A1 WO 2023081209A1 US 2022048700 W US2022048700 W US 2022048700W WO 2023081209 A1 WO2023081209 A1 WO 2023081209A1
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- Prior art keywords
- compound
- cancer
- pharmaceutically acceptable
- acceptable salt
- methyl
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- 239000003112 inhibitor Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical group O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
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- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
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- 230000000155 isotopic effect Effects 0.000 description 1
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- 238000002372 labelling Methods 0.000 description 1
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 238000000504 luminescence detection Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
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- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- TZQFXIYFLBBLQJ-UHFFFAOYSA-N methyl 2-bromo-6-fluorobenzoate Chemical compound COC(=O)C1=C(F)C=CC=C1Br TZQFXIYFLBBLQJ-UHFFFAOYSA-N 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- 125000005593 norbornanyl group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
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- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
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- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical group C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Definitions
- the present application relates generally to compounds that are PI3K inhibitors and methods of using them to treat conditions characterized by abnormal or excessive cellular proliferation, such as cancer and tumors.
- Phosphoinositide 3-kinases are a family of enzymes capable of phosphorylating the 3-hydroxyl group of the inositol ring of phosphatidylinositol. See Vanhaesebroeck, B., Perry, M.W.D., Brown, J.R. et al. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov 20, 741-769 (2021).
- An embodiment provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
- X is C or N
- Y 1 is CH, O, S, N, NH or NCH 3 ;
- Y 2 is C or N
- Z 1 and Z 2 are independently CH or N; each - independently represents a single bond or a double bond, with the proviso that all chemical valencies are satisfied;
- W is C, CH, or N
- Ring A is an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted cycloalkyl, or an unsubstituted or a substituted bicyclic heteroaryl, wherein when the foregoing Ring A is substituted, it is substituted with one or more of -F, -Cl, -CN, -OH, an unsubstituted Ci-6 alkyl, an unsubstituted Ci-6 alkoxy or an unsubstituted Ci-6 haloalkyl;
- R 1 is H, Ci-C 6 alkyl or Ci-Ce alkenyl
- R 2 is unsubstituted or a substituted Ci-Ce alkyl or unsubstituted or a substituted Ci-C 6 alkenyl, wherein when the foregoing R 2 is substituted, it is substituted with one or more of a monocyclic heteroaryl, -OH, -F, -CN, -CO(NH2), -COOH, -CH2OH, - CH 3 , -CF 3 , or -CF 2 ; or
- R 1 and R 2 together with W form an optionally substituted 4-, 5-, 6-, or 7- membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl, wherein when the foregoing is substituted, it is substituted with one or more of -OH, - F, -CN, -CO(NH 2 ), -COOH, -CH2OH, -CH 3 , -CF 3 , -CF 2 , oraCi-C 6 alkyl;
- R 4 is H, -F, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OH, or -OCH 3 ;
- R 5 is H, -CH 3 , -CH 2 CH 3 , -CF 2 , -CF 3 , or -CONH 2 ;
- R 6 is -COOH, -CN, -CONH 2 , oxadiazolone, -B(OH) 2 , -PONH 2 , -PO(CH 3 ) 2 , -CONHCH 3 , -CONHCH 2 CF 3 , or -CONHCH 2 CHF 2 .
- Another embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
- Another embodiment provides a method for treating a cancer or a tumor comprising administering an effective amount of a compound as described herein, or a pharmaceutically active salt thereof, or a pharmaceutical composition of as described herein, to a subject having the cancer or the tumor.
- FIG. 1 illustrates Scheme 1, a general synthetic scheme for preparing embodiments of compounds of the Formula (I).
- FIG. 2 illustrates Scheme 2, a general synthetic scheme for preparing embodiments of compounds of the Formula (I).
- FIG. 3 illustrates Scheme 3, a general synthetic scheme for preparing embodiments of compounds of the Formula (I).
- PI3K is a promising target for the treatment of cancer.
- PI3K pathway is commonly mutated and aberrantly activated in many cancers and plays a central role in tumor cell proliferation and survival.
- Gain-of-function mutations in PIK3CA the gene encoding the pl 10a catalytic subunit of PI3K are amongst the most common somatic alterations in solid tumors. Treatments to target the PI3K pathway mutations selectively are desired to treat the mutant driven cancers.
- the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl,
- C a to Cb in which “a” and “b” are integers refer to the number of carbon atoms in a group.
- the indicated group can contain from “a” to “b”, inclusive, carbon atoms.
- a “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH 3 ) 2 CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CthhC-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.
- R groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle.
- R a and R b of an NR a R b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:
- alkyl refers to a fully saturated aliphatic hydrocarbon group.
- the alkyl moiety may be branched or straight chain.
- branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
- straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
- the alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
- the alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms.
- the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
- An alkyl group may be substituted or unsubstituted.
- alkylene refers to a bivalent fully saturated straight chain aliphatic hydrocarbon group.
- alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene.
- An alkylene group may be represented by followed by the number of carbon atoms, followed by a For example, to represent ethylene.
- the alkylene group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated).
- the alkylene group may also be a medium size alkyl having 1 to 12 carbon atoms.
- the alkylene group could also be a lower alkyl having 1 to 4 carbon atoms.
- An alkylene group may be substituted or unsubstituted.
- a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a C3-6 monocyclic cycloalkyl group (e.g., -C- ).
- alkenyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1 -propenyl, 2-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2- butenyl and the like. An alkenyl group may be unsubstituted or substituted.
- alkynyl refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like.
- An alkynyl group may be unsubstituted or substituted.
- cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
- Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
- a cycloalkyl group may be unsubstituted or substituted.
- mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro- IH-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[l.l.l]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro [4.5] decane.
- cycloalkenyl refers to a mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein).
- Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion.
- a cycloalkenyl group may be unsubstituted or substituted.
- aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic (such as bicyclic) aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
- the number of carbon atoms in an aryl group can vary.
- the aryl group can be a Ce-Cu aryl group, a Ce-Cio aryl group or a Cf> aryl group.
- Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
- An aryl group may be substituted or unsubstituted.
- heteroaryl refers to a monocyclic or multicyclic (such as bicyclic) aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
- heteroatoms for example, 1, 2 or 3 heteroatoms
- the number of atoms in the ring(s) of a heteroaryl group can vary.
- the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms.
- heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond.
- heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine
- heterocyclyl or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
- a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
- a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
- the term “fused” refers to two rings which have two atoms and one bond in common.
- the term “bridged heterocyclyl” or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non- adjacent atoms.
- the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge.
- Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
- five carbon atoms and one heteroatom four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom.
- heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
- heterocyclyl or heteroalicyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3- dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3- dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trio
- spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2- oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.
- aralkyl and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2- phenylalkyl, 3-phenylalkyl and naphthylalkyl.
- heteroarylkyl and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3 -thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.
- heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclic group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).
- hydroxy refers to a -OH group.
- alkoxy refers to the Formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
- R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
- a non- limiting list of alkoxy s are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n- butoxy, iso
- acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
- a “cyano” group refers to a “-CN” group.
- halogen atom or “halogen” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
- a thiocarbonyl may be substituted or unsubstituted.
- An O-carbamyl may be substituted or unsubstituted.
- An N-carbamyl may be substituted or unsubstituted.
- An O-thiocarbamyl may be substituted or unsubstituted.
- An N-thiocarbamyl may be substituted or unsubstituted.
- a C-amido may be substituted or unsubstituted.
- R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-amido may be substituted or unsubstituted.
- S-sulfonamido refers to a “-SO2N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An S-sulfonamido may be substituted or unsubstituted.
- N-sulfonamido refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-sulfonamido may be substituted or unsubstituted.
- An O-carboxy may be substituted or unsubstituted.
- An ester and C-carboxy may be substituted or unsubstituted.
- a “nitro” group refers to an “-NO2” group.
- a “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- a sulfenyl may be substituted or unsubstituted.
- a sulfinyl may be substituted or unsubstituted.
- a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
- haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri- haloalkyl and polyhaloalkyl).
- Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl.
- a haloalkyl may be substituted or unsubstituted.
- haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
- a halogen e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
- groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2- fluoroisobutoxy.
- a haloalkoxy may be substituted or unsubstituted.
- amino and “unsubstituted amino” as used herein refer to a -NH2 group.
- a “mono-substituted amine” group refers to a “-NHRA” group in which RA can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- the RA may be substituted or unsubstituted.
- a mono-substituted amine group can include, for example, a mono-alkylamine group, a mono-Ci -Ce alkylamine group, a monoarylamine group, a mono-Ce-Cio arylamine group and the like.
- mono- substituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.
- a “di-substituted amine” group refers to a “-NRARB” group in which RA and RB can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- RA and RB can independently be substituted or unsubstituted.
- a di-substituted amine group can include, for example, a di-alkylamine group, a di-Ci-Ce alkylamine group, a di-arylamine group, a di-Ce-Cio arylamine group and the like.
- Examples of di-substituted amine groups include, but are not limited to, -N(methyl)2, -N(phenyl) (methyl), -N (ethyl) (methyl) and the like.
- “mono-substituted amine(alkyl)” group refers to a mono-substituted amine as provided herein connected, as a substituent, via a lower alkylene group.
- a mono-substituted amine(alkyl) may be substituted or unsubstituted.
- a mono-substituted amine(alkyl) group can include, for example, a mono-alkylamine(alkyl) group, a mono-Ci-Ce alkylamine(Ci-C6 alkyl) group, a mono-arylamine(alkyl group), a mono- C6-C10 arylamine(Ci-C6 alkyl) group and the like.
- Examples of mono-substituted amine(alkyl) groups include, but are not limited to, -CH2NH(methyl), -CH2NH(phenyl), -CH 2 CH 2 NH(methyl), -CH 2 CH 2 NH(phenyl) and the like.
- di-substituted amine(alkyl) refers to a di-substituted amine as provided herein connected, as a substituent, via a lower alkylene group.
- a di-substituted amine(alkyl) may be substituted or unsubstituted.
- a di-substituted amine(alkyl) group can include, for example, a dialkylamine(alkyl) group, a di-Ci-Co alkylamine(Ci-C6 alkyl) group, a di-arylamine(alkyl) group, a di-Ce-Cio arylamine(Ci-C6 alkyl) group and the like.
- di-substituted amine(alkyl)groups include, but are not limited to, -CH2N(methyl)2, -CH2N(phenyl)(methyl), -NCH2(ethyl)(methyl), -CH2CH2N(methyl)2, -CH2CH2N(phenyl)(methyl), -NCH2CH2(ethyl)(methyl) and the like.
- substituents there may be one or more substituents present.
- haloalkyl may include one or more of the same or different halogens.
- C1-C3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
- a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
- a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
- the term “radical” can be used interchangeably with the term “group.”
- salts refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- the salt is an acid addition salt of the compound.
- Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate).
- Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2- oxopentanedioic or naphthalenesulfonic acid.
- an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
- Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine.
- a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as di
- a salt is formed by protonation of a nitrogen-based group (for example, NH2)
- the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NH 3 + ) and the positive charge can be balanced by a negatively charged counterion (such as Cl’ )•
- PI3K inhibition and similar terms refer to inhibiting the activity or function of a PI3K protein.
- PI3K inhibitor refers to an agent (including small molecules and proteins) that inhibits the function of PI3K protein.
- FRET fluorescence resonance energy transfer
- SPR surface plasmon resonance
- fluorescence polarization/anisotropy there are numerous methods of evaluating protein binding interactions, including, but not limited to co-immunoprecipitation, fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR) and fluorescence polarization/anisotropy .
- each center may independently be of R-configuration or S -configuration or a mixture thereof.
- the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture.
- each double bond may independently be E or Z a mixture thereof.
- all tautomeric forms are also intended to be included.
- valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
- hydrogens or isotopes thereof e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
- the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
- Each chemical element as represented in a compound structure may include any isotope of said element.
- a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
- the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
- hydrogen- 1 protium
- hydrogen-2 deuterium
- the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates.
- the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like.
- the compounds described herein exist in unsolvated form.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol.
- the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
- the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
- Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
- X in Formula (I) can be X is C or N.
- X is C.
- X is N.
- Y 1 in Formula (I) can be CH, O, S, or N, NH or NCH3.
- Y 1 is CH.
- Y 1 is NH.
- Y 1 is N.
- Y 1 is O.
- Y 1 is S.
- Y 1 is NCH3.
- Y 2 in Formula (I) can be C or N.
- Y 2 is C.
- Y 2 is N.
- Z 1 in Formula (I) can be CH or N.
- Z 1 is CH.
- Z 1 is N.
- Z 2 in Formula (I) can be CH or N.
- Z 2 is CH.
- Z 2 is N.
- Each - in Formula (I) can independently represent a single bond or a double bond.
- W in Formula (I) can be C, CH, or N.
- W is C.
- W is CH.
- W is N.
- Ring A in Formula (I) can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted cycloalkyl, or an unsubstituted or a substituted bicyclic heteroaryl, wherein when the foregoing are substituted, they are substituted with one or more of -F, -Cl, -CN, -OH, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy or an unsubstituted C1-6 haloalkyl.
- Ring A can be an unsubstituted or a substituted aryl.
- Ring A can be an unsubstituted or a substituted monocyclic heteroaryl. In another embodiment, Ring A can be an unsubstituted or a substituted cycloalkyl. In an embodiment, Ring A can be an unsubstituted or a substituted bicyclic heteroaryl.
- R 1 in Formula (I) can be H, a Ci-Ce alkyl or a Ci-Ce alkenyl.
- R 1 can be H.
- R 1 can be Ci-Ce alkyl.
- R 1 can be a Ci-Ce alkenyl.
- R 2 in Formula (I) can be R 2 can be an unsubstituted or a substituted Ci-Ce alkyl or unsubstituted or a substituted Ci-Ce alkenyl, wherein when the foregoing are substituted, they are substituted with one or more of -OH, -F, -CN, -CO(NH2), -COOH, - CH2OH, -CH3, -CF3, or -CF2.
- R 2 is an unsubstituted or a substituted Ci- Ce alkyl.
- R 2 is unsubstituted or a substituted Ci-Ce alkenyl.
- R 1 and R 2 taken together with W can form an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl, wherein when the foregoing are substituted, they are substituted with one or more of a monocyclic heteroaryl (e.g., pyrazole), -OH, -F, -CN, -CO(NH2), -COOH, -CH2OH, -CH3, -CF3, -CF2, or a Ci-C6 alkyl.
- R 1 and R 2 taken together with W can form an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle.
- R 1 and R 2 taken together with W can form an optionally substituted 5- or 6- membered heteroaryl.
- R 3 can be H.
- R 3 can be CN.
- R 3 can be a C1-C4 alkyl.
- R 3 can be -CHO.
- R 3 can be -CH2CN.
- R 3 can be -CH(CH3)CN. In another embodiment, R 3 can be - C(CH 3 ) 2 CN. In another embodiment, R 3 can be -CH 2 OH, -CH2NH2, -CH2CH2OH, - CH2CH2NH2, or -CHCONH2.
- R 4 in Formula (I) can be H, -F, -CN, -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -OH, or -OCH3.
- R 4 can be H, -F, -CN, or -CH3.
- R 4 can be -CH2CH3, -CH(CH 3 ) 2 , -OH, or -OCH3.
- R 5 in Formula (I) can be H, -CH 3 , -CH2CH3, -CF 2 , -CF3, or -CONH 2 .
- R 5 is H, -CH3, or -CH2CH3.
- R 5 is -CF2, -CF3, or -
- R 6 in Formula (I) can be -COOH, -CN, or -CONH2.
- R 6 can be -COOH.
- R 6 can be-CN.
- R 6 can be -CONH2.
- R 6 can be -CONH2, oxadiazolone, -B(OH)2, -PONH2, - PO(CH 3 )2, -CONHCH3, -CONHCH2CF3, or -CONHCH2CHF2.
- the compound of Formula (I) has a chemical structure selected from the following:
- the compound of Formula (I) has a chemical structure as described in Table A, Table B and/or the examples below. Chemical (IUPAC) names are also provided for the convenience of those skilled in the art. To the extent the
- IUPAC name is inconsistent with the structure, the structure is to be given greater weight.
- compositions that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
- composition refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers.
- the pharmaceutical composition facilitates administration of the compound to an organism.
- Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
- Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
- a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
- DMSO dimethyl sulfoxide
- a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable.
- a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
- a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
- an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
- stabilizers such as anti-oxidants and metal-chelating agents are excipients.
- the pharmaceutical composition comprises an anti-oxidant and/or a metalchelating agent.
- a “diluent” is a type of excipient.
- compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
- compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
- a compound, salt and/or composition include, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
- a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered orally.
- the liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.
- compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
- the pack may for example comprise metal or plastic foil, such as a blister pack.
- the pack or dispenser device may be accompanied by instructions for administration.
- the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
- Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for treatment of an indicated condition.
- Some embodiments described herein relate to a method for treating a cancer or a tumor described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer or tumor described herein.
- a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
- a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer or tumor described herein.
- inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer or a tumor described herein.
- Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer or a tumor described herein.
- Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor described herein that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
- Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor described herein.
- the use can include contacting the growth or the tumor with the medicament.
- Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor described herein.
- Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
- Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein.
- the use can include contacting the malignant growth or a tumor described herein with the medicament.
- Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for contacting a malignant growth or a tumor described herein, wherein the malignant growth or tumor is due to a cancer described herein.
- a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
- suitable malignant growths, cancers and tumors include, but are not limited to: breast cancer, brain cancer, prostate cancer, head and neck cancer, endometrial cancer, gastric cancer, lymphoma, ovarian cancer, lung cancer, colorectal cancer, non-small cell lung cancer, glioma, bladder cancer, soft tissue sarcoma, esophagogastric cancer, salivary gland cancer, thyroid cancer, hepatobiliary cancer, renal cell carcinoma, melanoma, pancreatic cancer, cervical cancer, and small bowel cancer.
- a “subject” refers to an animal that is the object of treatment, observation or experiment.
- Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
- “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
- the subject can be human.
- the subject can be a child and/or an infant, for example, a child or infant with a fever.
- the subject can be an adult.
- treat do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
- terapéuticaally effective amount and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated.
- a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
- the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration.
- the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
- an effective amount of a compound is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor.
- a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain.
- an effective amount, or a therapeutically effective amount of a PI3K inhibitor is the amount which results in the reduction in PI3K protein activity. Methods for measuring reductions in PI3K activity are known to those skilled in the art and can be determined by the analysis of PI3K binding, e.g., as illustrated in the Examples below.
- the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.
- a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg.
- a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between.
- the compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form.
- the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
- the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
- the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed.
- the determination of effective dosage levels can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies.
- useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine)
- Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
- MEC minimal effective concentration
- the MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
- Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
- the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
- the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
- Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods.
- the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
- the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods.
- the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
- FIG. 1 illustrates general synthetic Scheme 1 for preparing embodiments of compounds of Formula (I).
- R 3 , R 5 , WR*R 2 , and Ring A can be as described herein.
- the aromatic or heteroaromatic ring of la can be brominated with bromine, N- bromosuccinimide or other brominating agent to obtain lb.
- Ketone lb is reacted with carbondisulfide under basic conditions to obtain 1c where R 3 is hydrogen.
- the resultant 1c is reacted with ethyliodide to obtain Id.
- the bromide of Id can be displaced via a palladium- catalyzed Heck-reaction, Stille coupling to yield le.
- Id can be reacted with 2- methyl-vinylboronic acid followed by oxidative cleavage to give le.
- Ketone le can undergo a reductive amination with t-butylsulfinamine to obtain If.
- Those skilled in art will realize that If can be obtained in chirally pure form or the enantiomer excess can be enriched at this step to yield 1g.
- Removal of the t-butylsulfoxide group under acidic conditions provides 1 h.
- the subsequent reaction of Ih with the leaving group (i.e. bromide under Pd-catalyzed conditions or mesyl under basic conditions) of methyl- or t-butyl ester of li provides Ij.
- the sulfide of Ij can be directly reacted with a boronic acid under palladium-catalyzed, copper-mediated conditions, followed by ester hydrolysis to obtain IA, a compound of Formula (I).
- sulfide of Ij can be oxidized to sulfone Ik that undergoes nucleophilic displacement with a primary or secondary amine, followed by ester hydrolysis to obtain IA.
- Conversion of R 3 from hydrogen to halogen (F, Cl, Br, I) and from iodo to cyano can occur either at If, 1g or Ij or before the ester hydrolysis prior to obtaining IA.
- FIG. 2 illustrates general synthetic Scheme 2 for preparing embodiments of compounds of Formula (I).
- R 3 , R 5 , WR*R 2 , and Ring A can be as described herein.
- Aminopyridine 2a can be reacted with diester 2n to obtain 2b.
- the hydroxypyridine of 2b can be mesylated and displaced by an amine nucleophile to obtain 2c.
- the bromide of 2c can be displaced via a palladium-catalyzed Heck-reaction, Stille coupling to yield 2d.
- 2c can be reacted with 2-methyl-vinylboronic acid followed by oxidative cleavage to give 2d.
- Ketone 2d can undergo a reductive amination with t-butylsulfinamine to obtain 2e.
- Those skilled in art will realize that 2e can be obtained in chirally pure form or the enantiomer excess can be enriched at this step to yield chirally pure 2e.
- Removal of the t- butylsulfoxide group under acidic conditions provides 2f.
- the subsequent reaction of 2f with the leaving group (i.e. bromide under Pd-catalyzed conditions or mesyl under basic conditions) of methyl- or t-butyl ester of 2o provides IIA.
- hydroxypyridine of 2b can be chlorinated to obtain 2g, that undergoes nucleophilic displacement with methylsulfide to obtain 2h.
- the bromide of 2h can be displaced via a palladium-catalyzed Heck-reaction, Stille coupling to yield 2i.
- 2h can be reacted with 2-methyl-vinylboronic acid followed by oxidative cleavage to give 2i.
- Ketone 2i can undergo a reductive amination with t- butylsulfinamine to obtain 2j. Removal of the t-butylsulfoxide group under acidic conditions provides 2k.
- the subsequent reaction of 2k with the leaving group e.g.
- sulfide of 21 can be reacted with a boronic acid under palladium-catalyzed, copper- mediated conditions, followed by ester hydrolysis to obtain IIA, a compound of Formula (I).
- sulfide of 21 can be oxidized to sulfone 2m that undergoes nucleophilic displacement with a primary or secondary amine, followed by ester hydrolysis to obtain IIA.
- Conversion of R 3 from hydrogen to iodide and to cyano can occur either at If, 1g or Ij or before the ester hydrolysis prior to obtaining IIA.
- Conversion of R 3 from hydrogen to halogen (F, Cl, Br, I) and from iodo to cyano can occur either at 2e, 2j or 21 or before the ester hydrolysis prior to obtaining IIA.
- FIG. 3 illustrates general synthetic Scheme 3 for preparing embodiments of compounds of Formula (I).
- R 3 , R 5 , WR*R 2 , and Ring A can be as described herein.
- the carboxylic acid of 3a can be treated under amide coupling conditions with R 3 -NH2 to obtain 3b.
- Amide 3b is treated with triphosgene under heat to obtain 3c.
- the hydroxyl group of 3c is chlorinated to obtain 3d, that is further reacted with an amine nucleophile to obtain 3e.
- the bromide of 3e can undergo a Suzuki reaction with a 2-methylvinylboronate to obtain 3f.
- Oxidative cleavage of 3f results in ketone 3g that is reduced to alcohol 3h.
- Alcohol 3h is treated with mesylchloride to obtain mesylate 3i that is displaced with amine 3k to obtain 3j.
- Ester hydrolysis of 3j provides IIIA, a compound of Formula (I).
- Step 2 Preparation of 9-bromo-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2- a]pyrimidin-4-one
- TEA 4.9 mL, 35.2 mmol
- 4,4-dimethylpiperidine hydrochloride 3.18 g, 21.3 mmol
- the reaction was stirred at 50 °C for 24 h.
- the reaction was cooled to rt, quenched with water (25 mL) and the mixture was extracted with DCM (2 x 25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated.
- Step 3 Preparation of 9-acetyl-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2- a]pyrimidin-4-one
- Step 4 Preparation of (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide
- Step 5 Preparation of (R)-9-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H- pyrido[ 1 ,2-a]pyrimidin-4-one
- Step 6 Preparation of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
- Step 7 Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
- Step 1 Preparation of ethyl 2-bromo-3-hydroxy-6-methylisonicotinate
- Step 3 Preparation of 2-bromo-3-hydroxy-A nctlu)xy-A / -mcthoxy-A / ,6- dimethylisonicotinamide
- Step 4 Preparation of l-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-l-one
- Step 7 Preparation of 8-bromo-2-(ethylsulfonyl)-6-methyl-4/Z-pyrano[2,3-c]pyridin-4-one
- Step 9 Preparation of 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z-pyrano[2,3- c]pyridine-4-one
- Step 10 Preparation of N-((R)-l-(2,(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- pyrano[2,3-c]pyridine-8-yl)ethyl)-2-methylpropane-2-sulfinamide
- the precipitate was removed by filtration through a celite pad that was washed with EtOAc (3 x 20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (40 mL). The combined organic layers were washed with water (75 mL) and brine (100 mL). The organic layer was then dried (Na2SO4) and filtered, then concentrated. The residue was dissolved in THF (12 mL) and AcOH (1.15 g, 19.2 mmol) and NaCNBHs (0.450 g, 7.19 mmol) were added at -15 °C. The resulting mixture was stirred at rt for 10 h.
- Step 11 Preparation of (R)-8-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z- pyrano[2,3-c]pyridin-4-one [0137] To a stirred solution of N-((R)-l-(2,(4,4-dimethylpiperidin-l-yl)-6-methyl- 4-oxo-4H-pyrano[2,3-c]pyridine-8-yl)ethyl)-2-methylpropane-2-sulfinamide (0.600 g, 1.48 mmol) in 1,4-dioxane (3 mL) was added HC1 (4M in 1,4-dioxane, 6 mL).
- Step 12 Preparation of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo- 4/Z-pyrano[2,3-c]pyridin-8-yl)ethylamino)benzoate
- Step 13 Preparation of (R)-2-((l-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4/Z- pyrano [2,3 -c]pyridin- 8-yl] ethylamino )benzoic acid
- Step 1 Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
- Step 2 Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
- Step 3 Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- Step 4 Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-3- vinyl-4H-chromen-8-yl)ethyl)amino)benzoate
- Step 5 Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)- 6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- Step 5 Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid
- Step 1 Preparation of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[ 1 ,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoate
- Step 2 Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid
- Step 1 Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-
- Step 2 Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-fluoro-7-methyl- 4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
- Step 1 Preparation of tert-butyl (R)-2-((l-(3-chloro-2-(4,4-dimethylpiperidin-l-yl)-7-methyl- 4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
- Step 2 Preparation of (R)-2-((l-(3-chloro-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo- 4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
- Step 1 Preparation of tert-butyl 2-(((R)-l-(2-3-(lH-pyrazol-4-yl)piperidin-l-yl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate [0154] To a stirred solution of tert-butyl (R)-2-((l-(2-(ethylsulfonyl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate (400 mg, 0.848 mmol) and 3-(lH-pyrazol-4- yl)piperidine dihydrochloride (228 mg, 1.02 mmol) in DCM (4 mL) was added DIPEA (0.444 mL, 2.50 mmol) at 0 °C.
- Step 2 Preparation of 2-(((R)-l-(2-((R)-3-(lH-Pyrazol-4-yl)piperidin-l-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoic acid and 2-(((R)-l-(2-((S)-3-(lH-Pyrazol-4- yl)piperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid
- Step 1 Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-7-methyl-
- Step 2 Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-
- Step 3 Preparation of (R)-2-((l-(3-cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo- 4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
- Step 1 Preparation of l-(3-bromo-2-hydroxy-5-methylphenyl)ethan- 1-one
- Step 7 Preparation of (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)-2-methylpropane-2-sulfinamide
- Step 8 Preparation of (R)-8-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4H- chromen-4-one
- Step 9 Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-
- Step 10 Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-6-methyl- 4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- Step 11 Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-
- Step 12 Preparation of tert-butyl 2-(((lR)-l-(3-(l,2-dihydroxyethyl)-2-(4,4- dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate [0170] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)- 6-methyl-4-oxo-3-vinyl-4H-chromen-8-yl)ethyl)amino)benzoate (700 mg, 1.36 mmol) in acetone (7 mL) and water (7 mL) were added potassium osmate dihydrate (25 mg, 0.067 mmol) and 4-methyl morpholine-N-oxide (274 mg, 2.03 mmol).
- Step 13 Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-formyl-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- Step 14 Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoic acid [0172] (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo-
- 4H-chromen-8 yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l-(2-(4,4- dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following the procedure for Step 3 of Example 6 to obtain the title compound (11 mg, 22%).
- Step 2 Preparation of (R)-N-((R)-l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)- 2-methylpropane-2-sulfinamide
- Step 4 Preparation of tert-butyl (R)-2-((l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate
- Step 5 Preparation of tert-butyl (R)-2-((l-(2-(ethylsulfonyl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate
- Step 6 Preparation of tert-butyl (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoate
- Step 7 Preparation of tert-butyl (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-3-iodo-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- tert-Butyl (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-3-iodo-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2-(4,4- difluoropiperidin- l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 10 of Example 11 to afford the title compound (155 mg, 85%). MS (ESI) 625.6 [M+H] + .
- Step 8 Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl- 4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- tert-Butyl (R)-2-((l-(3-cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2-(4,4- difluoropiperidin-l-yl)-3-iodo-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 2 of Example 10 to afford the title compound (103 mg, 80%).
- Step 9 Preparation of (R)-2-((l-(3-cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
- Step 1 Preparation of tert-butyl (R)-2-((l-(6-methyl-2-(6-methylpyridin-2-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
- Step 2 Preparation of (R)-2-((l-(6-Methyl-2-(6-methylpyridin-2-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
- Step 2 Preparation of 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3/f)-one [0187]
- Triphosgene (0.400 g, 1.33 mmol) was added into a flask containing 2- amino-3-bromo-N, 5 -dimethylbenzamide (0.81 g, 3.33 mmol) in CH2CI2 (33.3 mL).
- the reaction was heated under reflux for 19 h. After cooling to rt, the reaction was concentrated under reduced pressure to afford 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3H)-one (0.91 g, 101%), which was taken to the next step without further purification.
- Step 5 Preparation of 2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-8-(prop-l-en-2- yl)quinazolin-4(3/f)-one
- 1,4-Dioxane was removed under pressure then diluted with ethyl acetate and washed with water and brine. The aqueous layer was back extracted with EtOAc (lx). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/Hex) to afford 2-(4,4-dimethylpiperidin- l-yl)-3,6-dimethyl-8-(prop-l-en-2-yl)quinazolin-4(3/f)-one (1.01 g, 97%).
- Step 6 Preparation of 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethylquinazolin-4(3/f)-
- reaction mixture was stirred at rt for 1 h.
- the reaction mixture was diluted with water then washed with CH2CI2 (2x).
- the combined organic layers were washed with brine, dried (MgSCL), filtered, and concentrated.
- the residue was purified by flash chromatography (SiO2, EtOAc/Hex) to afford 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethylquinazolin- 4(3H)-one (0.57 g, 57%).
- Step 7 Preparation of 2-(4,4-dimethylpiperidin-l-yl)-8-(l -hydroxy ethyl)-3, 6- dimethylquinazolin-4(3//)-one
- Step 8 Preparation of l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl methanesulfonate
- Step 9 Preparation of methyl 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate
- Step 10 Preparation of 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid
- Lithium hydroxide monohydrate (2N, 0.069 mL, 0.14 mmol) was added into a stirred suspension of methyl 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (0.016 g, 0.035 mmol) in MeOH (1.0 mL) and THF (0.50 mL) at rt. The resulting solution was heated at 60 °C overnight. After cooling down to 0 °C, HC1 (2N, aqueous) was added to adjust the pH to 2.
- Step 1 Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzohydrazide
- Step 2 Preparation of (R)-5-(2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one
- Step 2 Preparation of (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzohydrazide
- Step 3 Preparation of (R)-5-(2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one
- Step 1 Preparation of tert-butyl (R)-2-((l-(2-(4-cyano-4-methylpiperidin-l-yl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- tert-Butyl (R)-2-((l-(2-(4-cyano-4-methylpiperidin-l-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2- (ethylsulfonyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate and 4- methylpiperidine-4-carbonitrile hydrochloride following a procedure similar to that used for Step 5 of Example 11 to afford the title compound (0.270 g, 68%).
- Step 2 Preparation of (R)-2-((l-(2-(4-cyano-4-methylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
- Step 1 Preparation of tert-butyl (R)-2-((l-(2-(ethylthio)-3-iodo-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
- N-iodosuccinimide (0.635 g, 2.82 mmol) was added as a solid to tert-butyl (R)-2-((l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (1.24 g, 2.82 mmol) in 6 mL 1,2-DCE at 0 °C. The ice bath was removed and the reaction was stirred for 12 h at rt. 100 mg of N-iodosuccinimide was added and the reaction was stirred at rt for 1 h.
- Step 2 Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(ethylthio)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
- Step 3 Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(l,4-dimethyl-lH-pyrazol-3-yl)-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
- Step 4 Preparation of (R)-2-((l-(3-cyano-2-(l,4-dimethyl-lH-pyrazol-3-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoic acid formic acid salt
- Step 1 Preparation of methyl 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate
- Step 2 Preparation of (S)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid
- Examples 29-39 are prepared using procedures similar to those described for Examples 1-28, including selection of appropriate starting materials that may be readily obtained from commercial sources, prepared by known and/or published procedures, or provided as otherwise described herein. Structures, IUPAC names and selected analytical data for compounds are summarized in Table B.
- ADP-Glo assay was used to measure inhibition of lipid kinase activity of PI3Ka (pl l0a/p85a) and PI3K (pl l0a(H1047R)/p85a) with ligands.
- the kinase reactions utilized ATP and produced ADP as a byproduct.
- the ADP production was quantified by ADP- Glo luminescence detection.
- the kinase reaction with lipid substrate PI(4,5)P2:PS (10 pM) was carried out in the presence of ATP (10 pM), the reaction was quenched and remaining ATP was depleted with ADP-GloTM reagent.
- ADP was converted to ATP which was measured using a luciferase/luciferin reaction.
- the substrate PI(4,5)P2:PS
- the kinase was delivered into the substrate solution and gently mixed.
- the compounds were delivered in 100% DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), and incubated for 20 min at room temperature.
- ATP was delivered into the reaction mixture to initiate the reaction and the mixture was incubated for 60 min at 30 °C.
- the reaction was quenched with ADP-Glo reagent and incubated for 40 min. Detection mixture was added and the mixture incubated for 30 min.
- Luminescence was measured and converted into pM ADP production based on ADP standard curves. The nonlinear regression to obtain the standard curve and IC50 values were performed using Graphpad Prism software.
- a large ratio between the wild-type (WT) (PI3Ka (pl 10a/p85a) and H1047R mutant (PI3K (pl l0a(H1047R)/p85a) IC50 indicates compounds that are active in H1047R assay and less active in the wild type.
- Activity in the WT may result in toxicities, such as hyperglycemia, hyperinsulinemia, gastrointestinal toxicity and rash, thus compounds that preferentially inhibit H104R mutant are beneficial because they reduce toxicities.
- Compound Toxicity was evaluated in in T47D cells using a Cell Titer-Gio (CTG) Assay.
- the T47D cells were cultured in RPMI1640 medium with 10% FBS and 1% penicillin/streptomycin. The culture medium was removed, the cells were treated with 0.25% trypsin and cell number counted with Vi-CELL XR Cell Viability Analyzer. The cells were plated (3000 cells/100 uL) on 96-well plate and incubated overnight. The cells were treated with compounds at various concentrations in DMSO and incubated for 5 days. The plates were removed from the incubator and let to cool to rt over 30 min.
- inhibition% (ZPE-X)/(ZPE-HPE)*100% and XL Fit software was used to calculate IC50 values.
- A is ⁇ 250 nM
- C is >500 nM and ⁇ 1000 nM
- D is > 1000 nM and ⁇ 5,000
- E is > 5000 nM and ⁇ 10,000 nM
Abstract
Compounds of Formula (I) and pharmaceutically active salts thereof are provided, where the variables in Formula (I) are described herein. Such compounds and salts are PI3K inhibitors that are useful for treating conditions characterized by abnormal or excessive cellular proliferation, such as cancer and tumors.
Description
PI3K INHIBITORS AND METHODS OF TREATING CANCER
INCORPORATION BY REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S Provisional Application Serial No. 63/263,509, filed November 3, 2021, and U.S Provisional Application Serial No. 63/267,959, filed February 14, 2022, both of which are hereby incorporated herein by reference in their entireties for all purposes.
BACKGROUND
Field
[0002] The present application relates generally to compounds that are PI3K inhibitors and methods of using them to treat conditions characterized by abnormal or excessive cellular proliferation, such as cancer and tumors.
Description
[0003] Phosphoinositide 3-kinases (PI3K) are a family of enzymes capable of phosphorylating the 3-hydroxyl group of the inositol ring of phosphatidylinositol. See Vanhaesebroeck, B., Perry, M.W.D., Brown, J.R. et al. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov 20, 741-769 (2021).
[0004] A number of compounds of varying chemical structure that inhibit PI3K have been evaluated for their ability to treat cancer and/or tumors. For example, Table 1 illustrates several PI3K inhibitors that have progressed in the United States FDA approval process.
[0005] The clinical advances of multiple compounds represent milestones in the development of PI3K inhibitors. However, there remains a need for improved compounds that inhibit the activity of PI3K.
SUMMARY
[0006] Various embodiments provide compounds of the Formula (I) and methods of using them.
[0007] An embodiment provides a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is C or N;
Y1 is CH, O, S, N, NH or NCH3;
Y2 is C or N;
Z1 and Z2 are independently CH or N; each - independently represents a single bond or a double bond, with the proviso that all chemical valencies are satisfied;
W is C, CH, or N;
Ring A is an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted cycloalkyl, or an unsubstituted or a substituted bicyclic heteroaryl, wherein when the foregoing Ring A is substituted, it is substituted with one or more of -F, -Cl, -CN, -OH, an unsubstituted Ci-6 alkyl, an unsubstituted Ci-6 alkoxy or an unsubstituted Ci-6 haloalkyl;
R1 is H, Ci-C6 alkyl or Ci-Ce alkenyl;
R2 is unsubstituted or a substituted Ci-Ce alkyl or unsubstituted or a substituted Ci-C6 alkenyl, wherein when the foregoing R2 is substituted, it is substituted with one or more of a monocyclic heteroaryl, -OH, -F, -CN, -CO(NH2), -COOH, -CH2OH, - CH3, -CF3, or -CF2; or
R1 and R2 together with W form an optionally substituted 4-, 5-, 6-, or 7- membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl,
wherein when the foregoing is substituted, it is substituted with one or more of -OH, - F, -CN, -CO(NH2), -COOH, -CH2OH, -CH3, -CF3, -CF2, oraCi-C6 alkyl;
R3 is H, -CN, -CHO, -CH=CH2, -CH2CN, -CH(CH3)CN, -C(CH3)2CN, a C1-C4 alkyl, -CH2OH, -CH2NH2, -CH2CH2OH, -CH2CH2NH2, or -CHCONH2;
R4 is H, -F, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OH, or -OCH3;
R5 is H, -CH3, -CH2CH3, -CF2, -CF3, or -CONH2; and
R6 is -COOH, -CN, -CONH2, oxadiazolone, -B(OH)2, -PONH2, -PO(CH3)2, -CONHCH3, -CONHCH2CF3, or -CONHCH2CHF2.
[0008] Another embodiment provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[0009] Another embodiment provides a method for treating a cancer or a tumor comprising administering an effective amount of a compound as described herein, or a pharmaceutically active salt thereof, or a pharmaceutical composition of as described herein, to a subject having the cancer or the tumor.
[0010] These and other embodiments are described in greater detail below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 illustrates Scheme 1, a general synthetic scheme for preparing embodiments of compounds of the Formula (I).
[0012] FIG. 2 illustrates Scheme 2, a general synthetic scheme for preparing embodiments of compounds of the Formula (I).
[0013] FIG. 3 illustrates Scheme 3, a general synthetic scheme for preparing embodiments of compounds of the Formula (I).
DETAILED DESCRIPTION
[0014] PI3K is a promising target for the treatment of cancer. PI3K pathway is commonly mutated and aberrantly activated in many cancers and plays a central role in tumor cell proliferation and survival. Gain-of-function mutations in PIK3CA, the gene encoding the pl 10a catalytic subunit of PI3K are amongst the most common somatic alterations in solid
tumors. Treatments to target the PI3K pathway mutations selectively are desired to treat the mutant driven cancers.
Definitions
[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0016] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amine group, a di-substituted amine group, a mono- substituted amine(alkyl) and a di-substituted amine(alkyl).
[0017] As used herein, “Ca to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in a group. The indicated group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CthhC-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.
[0018] If two “R” groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if Ra and Rb of an NRaRb group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:
[0019] As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted.
[0020] As used herein, the term “alkylene” refers to a bivalent fully saturated straight chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene. An alkylene group may be represented by followed by the number of carbon atoms, followed by a
For example,
to represent ethylene. The alkylene group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated). The alkylene group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkylene group could also be a lower alkyl having 1 to 4 carbon atoms. An alkylene group may be substituted or unsubstituted. For example, a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a C3-6
monocyclic cycloalkyl group (e.g., -C- ).
[0021] The term “alkenyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1 -propenyl, 2-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2- butenyl and the like. An alkenyl group may be unsubstituted or substituted.
[0022] The term “alkynyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted.
[0023] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro- IH-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[l.l.l]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro [4.5] decane.
[0024] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected
together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.
[0025] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic (such as bicyclic) aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a Ce-Cu aryl group, a Ce-Cio aryl group or a Cf> aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.
[0026] As used herein, “heteroaryl” refers to a monocyclic or multicyclic (such as bicyclic) aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.
[0027] Those skilled in the art understand that the partial circle in the fused “A” ring of the following moiety indicates that the “A” ring is aromatic:
[0028] For example, when any one or more of Qi, Q2 and Q3 is nitrogen, the above moiety is a heteroaryl group. Similarly, when Qi, Q2 and Q3 are all carbon, the above moiety is an aryl group.
[0029] As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-) and nitrogen (e.g., -N=, -NH- or -N(alkyl)-). A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged heterocyclyl” or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non- adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogens in a heteroalicyclic may be quatemized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups
include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3- dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3- dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of spiro heterocyclyl groups include 2-azaspiro[3.3]heptane, 2- oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.
[0030] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2- phenylalkyl, 3-phenylalkyl and naphthylalkyl.
[0031] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3 -thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.
[0032] A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).
[0033] As used herein, the term “hydroxy” refers to a -OH group.
[0034] As used herein, “alkoxy” refers to the Formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-
limiting list of alkoxy s are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.
[0035] As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
[0036] A “cyano” group refers to a “-CN” group.
[0037] The term “halogen atom” or “halogen” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
[0038] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.
[0039] An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.
[0040] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.
[0041] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.
[0042] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.
[0043] A “C-amido” group refers to a “-C(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.
[0044] An “N-amido” group refers to a “RC(=O)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.
[0045] An “S-sulfonamido” group refers to a “-SO2N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.
[0046] An “N-sulfonamido” group refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.
[0047] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.
[0048] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.
[0049] A “nitro” group refers to an “-NO2” group.
[0050] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.
[0051] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.
[0052] A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
[0053] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri- haloalkyl and polyhaloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl. A haloalkyl may be substituted or unsubstituted.
[0054] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2- fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
[0055] The terms “amino” and “unsubstituted amino” as used herein refer to a -NH2 group.
[0056] A “mono-substituted amine” group refers to a “-NHRA” group in which RA can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. The RA may be substituted or unsubstituted. A mono-substituted amine group can include, for example, a mono-alkylamine group, a mono-Ci -Ce alkylamine group, a monoarylamine group, a mono-Ce-Cio arylamine group and the like. Examples of mono- substituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.
[0057] A “di-substituted amine” group refers to a “-NRARB” group in which RA and RB can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. RA and RB can independently be substituted or unsubstituted. A di-substituted amine group can include, for example, a di-alkylamine group, a di-Ci-Ce alkylamine group, a di-arylamine group, a di-Ce-Cio arylamine group and the like. Examples of di-substituted amine groups include, but are not limited to, -N(methyl)2, -N(phenyl) (methyl), -N (ethyl) (methyl) and the like.
[0058] As used herein, “mono-substituted amine(alkyl)” group refers to a mono-substituted amine as provided herein connected, as a substituent, via a lower alkylene group. A mono-substituted amine(alkyl) may be substituted or unsubstituted. A mono-substituted amine(alkyl) group can include, for example, a mono-alkylamine(alkyl)
group, a mono-Ci-Ce alkylamine(Ci-C6 alkyl) group, a mono-arylamine(alkyl group), a mono- C6-C10 arylamine(Ci-C6 alkyl) group and the like. Examples of mono-substituted amine(alkyl) groups include, but are not limited to, -CH2NH(methyl), -CH2NH(phenyl), -CH2CH2NH(methyl), -CH2CH2NH(phenyl) and the like.
[0059] As used herein, “di-substituted amine(alkyl)” group refers to a di-substituted amine as provided herein connected, as a substituent, via a lower alkylene group. A di-substituted amine(alkyl) may be substituted or unsubstituted. A di-substituted amine(alkyl) group can include, for example, a dialkylamine(alkyl) group, a di-Ci-Co alkylamine(Ci-C6 alkyl) group, a di-arylamine(alkyl) group, a di-Ce-Cio arylamine(Ci-C6 alkyl) group and the like. Examples of di-substituted amine(alkyl)groups include, but are not limited to, -CH2N(methyl)2, -CH2N(phenyl)(methyl), -NCH2(ethyl)(methyl), -CH2CH2N(methyl)2, -CH2CH2N(phenyl)(methyl), -NCH2CH2(ethyl)(methyl) and the like.
[0060] Where the number of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.
[0061] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term “radical” can be used interchangeably with the term “group.”
[0062] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2-
oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH2), the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NH3 +) and the positive charge can be balanced by a negatively charged counterion (such as Cl’ )•
[0063] The term “PI3K inhibition” and similar terms refer to inhibiting the activity or function of a PI3K protein. Similarly, the term “PI3K inhibitor” refers to an agent (including small molecules and proteins) that inhibits the function of PI3K protein. As will be understood by those of skill in the art, there are numerous methods of evaluating protein binding interactions, including, but not limited to co-immunoprecipitation, fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR) and fluorescence polarization/anisotropy .
[0064] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S -configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.
[0065] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
[0066] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[0067] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
[0068] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
[0069] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited
elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
[0070] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
Compounds
[0071] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
[0072] X in Formula (I) can be X is C or N. For example, in an embodiment, X is C. In another embodiment, X is N.
[0073] Y1 in Formula (I) can be CH, O, S, or N, NH or NCH3. For example, in an embodiment, Y1 is CH. In another embodiment, Y1 is NH. In another embodiment, Y1 is N. In another embodiment, Y1 is O. In another embodiment, Y1 is S. In another embodiment, Y1 is NCH3.
[0074] Y2 in Formula (I) can be C or N. For example, in an embodiment, Y2 is C. In another embodiment, Y2 is N.
[0075] Z1 in Formula (I) can be CH or N. For example, in an embodiment, Z1 is CH. In another embodiment, Z1 is N.
[0076] Z2 in Formula (I) can be CH or N. For example, in an embodiment, Z2 is CH. In another embodiment, Z2 is N.
[0077] Each - in Formula (I) can independently represent a single bond or a double bond.
[0078] W in Formula (I) can be C, CH, or N. For example, in an embodiment, W is C. In another embodiment, W is CH. In another embodiment, W is N.
[0079] Ring A in Formula (I) can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted cycloalkyl, or an unsubstituted or a substituted bicyclic heteroaryl, wherein when the foregoing are substituted, they are substituted with one or more of -F, -Cl, -CN, -OH, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy or an unsubstituted C1-6 haloalkyl. In an embodiment, Ring A can be an unsubstituted or a substituted aryl. In another embodiment, Ring A can be
an unsubstituted or a substituted monocyclic heteroaryl. In another embodiment, Ring A can be an unsubstituted or a substituted cycloalkyl. In an embodiment, Ring A can be an unsubstituted or a substituted bicyclic heteroaryl.
[0080] R1 in Formula (I) can be H, a Ci-Ce alkyl or a Ci-Ce alkenyl. In an embodiment, R1 can be H. In another embodiment, R1 can be Ci-Ce alkyl. In another embodiment, R1 can be a Ci-Ce alkenyl.
[0081] R2 in Formula (I) can be R2 can be an unsubstituted or a substituted Ci-Ce alkyl or unsubstituted or a substituted Ci-Ce alkenyl, wherein when the foregoing are substituted, they are substituted with one or more of -OH, -F, -CN, -CO(NH2), -COOH, - CH2OH, -CH3, -CF3, or -CF2. In an embodiment, R2 is an unsubstituted or a substituted Ci- Ce alkyl. In another embodiment, R2 is unsubstituted or a substituted Ci-Ce alkenyl. In an alternative embodiment, R1 and R2 taken together with W can form an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl, wherein when the foregoing are substituted, they are substituted with one or more of a monocyclic heteroaryl (e.g., pyrazole), -OH, -F, -CN, -CO(NH2), -COOH, -CH2OH, -CH3, -CF3, -CF2, ora Ci-C6 alkyl. For example, in an embodiment, R1 and R2 taken together with W can form an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle. In another embodiment, R1 and R2 taken together with W can form an optionally substituted 5- or 6- membered heteroaryl.
[0082] R3 in Formula (I) can be H, -CN, -CHO, -CH=CH2, -CH2CN, - CH(CH3)CN, -C(CH3)2CN, a C1-C4 alkyl, -CH2OH, -CH2NH2, -CH2CH2OH, -CH2CH2NH2, or -CHCONH2. In an embodiment, R3 can be H. In another embodiment, R3 can be CN. In another embodiment, R3 can be a C1-C4 alkyl. In another embodiment, R3 can be -CHO. In another embodiment, R3 can be -CH=CH2. In another embodiment, R3 can be -CH2CN. In another embodiment, R3 can be -CH(CH3)CN. In another embodiment, R3 can be - C(CH3)2CN. In another embodiment, R3 can be -CH2OH, -CH2NH2, -CH2CH2OH, - CH2CH2NH2, or -CHCONH2.
[0083] R4 in Formula (I) can be H, -F, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OH, or -OCH3. In an embodiment, R4 can be H, -F, -CN, or -CH3. In another embodiment, R4 can be -CH2CH3, -CH(CH3)2, -OH, or -OCH3.
[0084] R5 in Formula (I) can be H, -CH3, -CH2CH3, -CF2, -CF3, or -CONH2. In an embodiment, R5 is H, -CH3, or -CH2CH3. In another embodiment, R5 is -CF2, -CF3, or -
CONH2.
[0085] R6 in Formula (I) can be -COOH, -CN, or -CONH2. In an embodiment, R6 can be -COOH. In another embodiment, R6 can be-CN. In another embodiment, R6 can be -CONH2. In another embodiment, R6 can be -CONH2, oxadiazolone, -B(OH)2, -PONH2, - PO(CH3)2, -CONHCH3, -CONHCH2CF3, or -CONHCH2CHF2.
[0086] Those skilled in the art understand that with respect to any particular compound of the Formula (I), X, Y1, Y2, Z1, Z2 and - in Formula (I) are selected together in such a way that the chemical valencies of the compound are satisfied, e.g., as illustrated by the compounds exemplified herein.
[0087] In various embodiments, the compound of Formula (I) has a chemical structure selected from the following:
[0088] In various embodiments, the compound of Formula (I) has a chemical structure as described in Table A, Table B and/or the examples below. Chemical (IUPAC) names are also provided for the convenience of those skilled in the art. To the extent the
IUPAC name is inconsistent with the structure, the structure is to be given greater weight.
Synthesis
[0089] Compounds of the Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein, including the Examples provided below. For example, in an embodiment, compounds of the Formula (I) are prepared in accordance with the general schemes illustrated in FIGS 1-3.
Pharmaceutical Compositions
[0090] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[0091] The term “pharmaceutical composition” refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
[0092] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.
[0093] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
[0094] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
[0095] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and/or a metalchelating agent. A “diluent” is a type of excipient.
[0096] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
[0097] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
[0098] Multiple techniques of administering a compound, salt and/or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection,
infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally.
[0099] One may also administer the compound, salt and/or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue- specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.
[0100] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for treatment of an indicated condition.
Uses and Methods of Treatment
[0101] Some embodiments described herein relate to a method for treating a cancer or a tumor described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer or tumor described herein. Other embodiments described herein relate to the
use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer or a tumor described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer or a tumor described herein.
[0102] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor described herein that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor described herein. In some embodiments, the use can include contacting the growth or the tumor with the medicament. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor described herein.
[0103] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. In some embodiments, the use can include contacting the malignant growth or a tumor described herein with the medicament. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for
contacting a malignant growth or a tumor described herein, wherein the malignant growth or tumor is due to a cancer described herein.
[0104] Examples of suitable malignant growths, cancers and tumors include, but are not limited to: breast cancer, brain cancer, prostate cancer, head and neck cancer, endometrial cancer, gastric cancer, lymphoma, ovarian cancer, lung cancer, colorectal cancer, non-small cell lung cancer, glioma, bladder cancer, soft tissue sarcoma, esophagogastric cancer, salivary gland cancer, thyroid cancer, hepatobiliary cancer, renal cell carcinoma, melanoma, pancreatic cancer, cervical cancer, and small bowel cancer.
[0105] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a child and/or an infant, for example, a child or infant with a fever. In other embodiments, the subject can be an adult.
[0106] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
[0107] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and
the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
[0108] For example, an effective amount of a compound is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (such as nonsmall cell lung cancer), a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain. As another example, an effective amount, or a therapeutically effective amount of a PI3K inhibitor is the amount which results in the reduction in PI3K protein activity. Methods for measuring reductions in PI3K activity are known to those skilled in the art and can be determined by the analysis of PI3K binding, e.g., as illustrated in the Examples below.
[0109] The amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.
[0110] In general, however, a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between. The compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form.
[0111] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
[0112] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine)
[0113] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0114] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods.
Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
[0115] Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
EXAMPLES
[0116] General synthetic routes for preparing compounds of Formula (I), including pharmaceutically acceptable salts, and intermediates are shown and described herein along with some examples of starting materials used to synthesize compounds described herein. Compounds and intermediates disclosed herein can be obtained using commercially available starting materials and reagents. Synthetic procedures will depend on particular substituents present in the compounds or intermediates, and various protection, deprotection or other well- known organic synthesis steps may be required but not necessarily illustrated in the generic schemes. Any steps shown in the generic schemes may be used in any combination or in different order to achieve the desired compounds or intermediates. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein.
[0117] FIG. 1 illustrates general synthetic Scheme 1 for preparing embodiments of compounds of Formula (I). In Scheme 1, R3, R5, WR*R2, and Ring A can be as described
herein. The aromatic or heteroaromatic ring of la can be brominated with bromine, N- bromosuccinimide or other brominating agent to obtain lb. Ketone lb is reacted with carbondisulfide under basic conditions to obtain 1c where R3 is hydrogen. The resultant 1c is reacted with ethyliodide to obtain Id. The bromide of Id can be displaced via a palladium- catalyzed Heck-reaction, Stille coupling to yield le. Alternatively, Id can be reacted with 2- methyl-vinylboronic acid followed by oxidative cleavage to give le. Ketone le can undergo a reductive amination with t-butylsulfinamine to obtain If. Those skilled in art will realize that If can be obtained in chirally pure form or the enantiomer excess can be enriched at this step to yield 1g. Removal of the t-butylsulfoxide group under acidic conditions provides 1 h. The subsequent reaction of Ih with the leaving group (i.e. bromide under Pd-catalyzed conditions or mesyl under basic conditions) of methyl- or t-butyl ester of li provides Ij. The sulfide of Ij can be directly reacted with a boronic acid under palladium-catalyzed, copper-mediated conditions, followed by ester hydrolysis to obtain IA, a compound of Formula (I). Alternatively, sulfide of Ij can be oxidized to sulfone Ik that undergoes nucleophilic displacement with a primary or secondary amine, followed by ester hydrolysis to obtain IA. Conversion of R3 from hydrogen to halogen (F, Cl, Br, I) and from iodo to cyano can occur either at If, 1g or Ij or before the ester hydrolysis prior to obtaining IA.
[0118] FIG. 2 illustrates general synthetic Scheme 2 for preparing embodiments of compounds of Formula (I). In Scheme 2, R3, R5, WR*R2, and Ring A can be as described herein. Aminopyridine 2a can be reacted with diester 2n to obtain 2b. The hydroxypyridine of 2b can be mesylated and displaced by an amine nucleophile to obtain 2c. The bromide of 2c can be displaced via a palladium-catalyzed Heck-reaction, Stille coupling to yield 2d. Alternatively, 2c can be reacted with 2-methyl-vinylboronic acid followed by oxidative cleavage to give 2d. Ketone 2d can undergo a reductive amination with t-butylsulfinamine to obtain 2e. Those skilled in art will realize that 2e can be obtained in chirally pure form or the enantiomer excess can be enriched at this step to yield chirally pure 2e. Removal of the t- butylsulfoxide group under acidic conditions provides 2f. The subsequent reaction of 2f with the leaving group (i.e. bromide under Pd-catalyzed conditions or mesyl under basic conditions) of methyl- or t-butyl ester of 2o provides IIA. Alternatively, hydroxypyridine of 2b can be chlorinated to obtain 2g, that undergoes nucleophilic displacement with methylsulfide to obtain 2h. The bromide of 2h can be displaced via a palladium-catalyzed Heck-reaction, Stille
coupling to yield 2i. Alternatively, 2h can be reacted with 2-methyl-vinylboronic acid followed by oxidative cleavage to give 2i. Ketone 2i can undergo a reductive amination with t- butylsulfinamine to obtain 2j. Removal of the t-butylsulfoxide group under acidic conditions provides 2k. The subsequent reaction of 2k with the leaving group (e.g. bromide under Pd- catalyzed conditions or mesyl under basic conditions) of methyl- or t-butyl ester of 2o provides 21. The sulfide of 21 can be reacted with a boronic acid under palladium-catalyzed, copper- mediated conditions, followed by ester hydrolysis to obtain IIA, a compound of Formula (I). Alternatively, sulfide of 21 can be oxidized to sulfone 2m that undergoes nucleophilic displacement with a primary or secondary amine, followed by ester hydrolysis to obtain IIA. Conversion of R3 from hydrogen to iodide and to cyano can occur either at If, 1g or Ij or before the ester hydrolysis prior to obtaining IIA. Conversion of R3 from hydrogen to halogen (F, Cl, Br, I) and from iodo to cyano can occur either at 2e, 2j or 21 or before the ester hydrolysis prior to obtaining IIA.
[0119] FIG. 3 illustrates general synthetic Scheme 3 for preparing embodiments of compounds of Formula (I). In Scheme 3, R3, R5, WR*R2, and Ring A can be as described herein. The carboxylic acid of 3a can be treated under amide coupling conditions with R3-NH2 to obtain 3b. Amide 3b is treated with triphosgene under heat to obtain 3c. The hydroxyl group of 3c is chlorinated to obtain 3d, that is further reacted with an amine nucleophile to obtain 3e. The bromide of 3e can undergo a Suzuki reaction with a 2-methylvinylboronate to obtain 3f. Oxidative cleavage of 3f results in ketone 3g that is reduced to alcohol 3h. Alcohol 3h is treated with mesylchloride to obtain mesylate 3i that is displaced with amine 3k to obtain 3j. Ester hydrolysis of 3j provides IIIA, a compound of Formula (I).
Example 1
(R)-2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid
Step 1: Preparation of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[l,2-a]pyrimidin-4-one
[0120] To a stirred solution of 3-bromo-5-methylpyridin-2-amine (2.50 g, 13.4 mmol) in DCM (25 mL) was added malonyl dichloride (1.96 g, 14.0 mmol) at 0 °C and the mixture was stirred at rt for 48 h. The reaction was quenched with water (25 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to afford crude 9-bromo-2-hydroxy-7-methyl- 4H-pyrido[l,2-a]pyrimidin-4-one (1.8 g, 51%), which was taken to the next step without further purification. MS (ESI) 255.0 [M+H]+.
Step 2: Preparation of 9-bromo-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2- a]pyrimidin-4-one
[0121] To a stirred solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[l,2- a]pyrimidin-4-one (1.80 g, 7.10 mmol) in DCM (18 mL) was added TEA (1.96 mL, 14.2 mmol) and the mixture was stirred for 10 min. Mesyl chloride (1.21 g, 10.7 mmol) was added drop-wise at 0 °C and the reaction was stirred at rt for 4 h. TEA (4.9 mL, 35.2 mmol) was added at 0 °C followed by 4,4-dimethylpiperidine hydrochloride (3.18 g, 21.3 mmol) and the reaction was stirred at 50 °C for 24 h. The reaction was cooled to rt, quenched with water (25 mL) and the mixture was extracted with DCM (2 x 25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/petroleum ether) to afford 9-bromo-2-(4,4-dimethylpiperidin-l-yl)-7-methyl- 4H-pyrido[l,2-a]pyrimidin-4-one (0.53 g, 21%). MS (ESI) 350.2 [M+H] +.
Step 3: Preparation of 9-acetyl-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2- a]pyrimidin-4-one
[0122] A stirred solution of 9-bromo-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H- pyrido[l,2-a]pyrimidin-4-one (1.00 g, 2.86 mmol) and tributyl(l -ethoxy vinyl) stannane (2.06 g, 5.72 mmol) in 1,4-dioxane (10 mL) was purged with N2 for 15 min. PdCh(PPh3)2 (200 mg, 0.286 mmol) was added and the reaction mixture was stirred at 90 °C for 24 h. The reaction was cooled to rt and 2N HC1 (25 mL) was added. The reaction mixture was stirred at 50 °C for 30 min. The reaction was cooled to rt and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiCL, EtOAc/petroleum ether) to afford 9-acetyl-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (500 mg, 55%). MS (ESI) 314.3 [M+H]+.
Step 4: Preparation of (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide
[0123] To a stirred solution of 9-acetyl-2-(4,4-dimethylpiperidin-l-yl)-7-methyl- 4H-pyrido[l,2-a]pyrimidin-4-one (0.500 g, 1.59 mmol) and (R)-2-methylpropane-2- sulfinamide (0.386 g, 3.19 mmol) in THF (4 mL) was added Ti(OEt)4 (2.18 g, 9.58 mmol). The reaction was stirred at 80 °C for 16 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was dissolved in THF (5 mL) and cooled to 0 °C. AcOH (0.577 g, 9.60 mmol) and NaCNBHs (0.226 g, 3.60 mmol) were added and the reaction was stirred at rt for 5 h. The reaction was quenched with water (5 mL) and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc/Pet. ether) to
afford (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2- a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (0.275 g, 40%). Chiral purity 98% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 419.5 [M+H]+.
Step 5: Preparation of (R)-9-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H- pyrido[ 1 ,2-a]pyrimidin-4-one
[0124] To a solution of (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4- oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (0.39 g, 0.93 mmol) in 1,4-dioxane (4 mL) was added 4M HC1 in dioxane (4 mL) at 0 °C. The reaction was stirred at rt for 2 h. The reaction was evaporated to dryness and triturated with diethyl ether. The residue was neutralized with saturated NaHCCh (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, DCM/MeOH) to afford (R)-9-(l- aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (0.27 g, 92%). Chiral purity 98% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 315.8 [M+H]+.
Step 6: Preparation of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
[0125] To a stirred solution of (R)-9-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l- yl)-7-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (0.200 g, 0.640 mmol) and methyl 2- bromobenzoate (0.163 g, 0.758 mmol) in 1,4-dioxane (4 mL) was added CS2CO3 (0.620 g, 1.91 mmol) and the reaction was purged with N2 for 15 min. Pd2(dba)3 (0.058 g, 0.064 mmol) and
XanthPhos (0.055 mg, 0.095 mmol) were added and the reaction was stirred at 95 °C for 16 h. The reaction was quenched with water (4 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/petroleum ether) to afford methyl (R)-2-((l- (2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (0.17 g, 60%). Chiral purity 98% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 449.5 [M+H]+.
Step 7: Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
[0126] To a stirred solution of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7- methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (0.170 mg, 0.379 mmol) in THF:MeOH (1:1, 2 mL) was added 2 M NaOH solution (1 mL, 2 mmol) at rt. The reaction was stirred at rt for 16 h. The reaction was neutralized in 2N HC1 and concentrated under reduced pressure. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The water layer was extracted with EtOAc (10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by chiral SFC (Chiralcel-ED-H (30 x 250 mm column) 20% MeOH) to afford (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7- methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (80 mg, 48%). 99.6% Chiral purity (Chiralcel-OD-3 (4.6 x 250 mm column) 20% MeOH); ’H NMR (400 MHz, DMSO-d6) 5 12.69 (s, 1H), 8.58-8.51 (m, 2H), 7.81 (d, 7=7.6 Hz, 1H), 7.55 (s, 1H), 7.18 (t, 7=7.2 Hz, 1H), 6.52 (t, 7=7.2 Hz, 1H), 6.32 (d, 7=8 Hz, 1H), 5.63 (s, 1H), 5.20 (s, 1H), 3.66 (m, 4H), 2.23 (s, 3H), 1.57-1.55 (d, 7=6.8 Hz, 3H), 1.38-1.35 (m, 4H), 0.98 (s, 6H); MS (ESI) 433.4 [M-H]-.
Example 2
(R)-2-((l-2-(4,4-Dimethylpiperidin-l-yl)-6-methyl-4-oxo-4/Z-pyrano[2,3-c]pyridin-8- yl]ethylamino)benzoic acid
[0127] To a stirred solution of ethyl 5-hydroxy-2-methylisonicotinate (22.0 g, 122 mmol) in DMF (220 mL) at 0 °C was added NBS (21.9 g, 122 mmol) and stirred at rt for 1 h. Upon completion, the reaction mixture was quenched with cold water (220 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4) and filtered, then concentrated to afford ethyl 2-bromo-3-hydroxy-6-methylisonicotinate (23 g, 72%). MS (ESI) 262.1 [M+H] +.
[0128] To a stirred solution of ethyl 2-bromo-3-hydroxy-6-methylisonicotinate (17.0 g, 65.7 mmol) in THF:MeOH:H2O (170 mL, 3:1:1) at 0 °C was added LiOH H2O (13.78 g, 328.3 mmol). The reaction mixture was stirred at rt for 16 h. Upon completion, the solvent was removed under reduced pressure. Water (25 mL) was added and the mixture was neutralized with 2N HC1. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4) and filtered and concentrated to afford 2-bromo-3- hydroxy-6-methylisonicotinic acid (13 g, 85%). MS (ESI) 232.0 [M+H]+.
[0129] To a stirred solution of 2-bromo-3-hydroxy-6-methylisonicotinic acid (5.50 g, 28.3 mmol) in DMF (55 mL) was added N,O-dimethyl hydroxylamine hydrochloride (4.10 g, 42.4 mmol), HATU (16.1 g, 42.4 mmol), and DIPEA (14.4 mL, 84.8 mmol) at 0 °C. The resulting mixture was stirred at rt for 16 h. Upon completion, the reaction mixture was quenched with cold water (30 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford 2-bromo-3-hydroxy- N-methoxy-N,6-dimethylisonicotinamide (2.8 g, 43%). MS (ESI) 275.1 [M+H]+.
[0130] To a stirred solution of 2-bromo-3-hydroxy-N-methoxy-N,6- dimethylisonicotinamide (3.00 g, 10.9 mmol) in THF (30 mL) was added 3M in THF MeMgBr (10.94 mL, 32.84 mmol) at 0 °C. The reaction was stirred at rt for 16 h. Upon completion, the reaction mixture was quenched with saturated NH4CI (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and filtered, then concentrated. The residue was purified by flash chromatography to afford l-(2-bromo-3-hydroxy-6- methylpyridin-4-yl)ethan-l-one (2.2 g, 87%). MS (ESI) 232.0 [M+H]+.
[0131] To a stirred solution of l-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan- 1-one (3.00 g, 13.0 mmol) in THF (60 mL) at -78 °C was added 2M NaHMDS in THF (9.80 mL, 19.6 mol). The reaction was then stirred at 0 °C for 1 h. The reaction was cooled to -78 °C and CS2 (1.20 mL, 19.6 mol) was added. The reaction was stirred at rt for 16 h. Upon
completion, it was cooled to -50°C and 15% H2SO4 was added drop-wise until the mixture was neutralized. The reaction was stirred for 30 min at rt then concentrated. The residue was triturated with DCM (30 mL) to afford 8-bromo-4-hydroxy-6-methyl-2/Z-pyrano[2,3- c]pyridine-2-thione (2.5 g, 70%) which was taken to the next step without further purification. MS (ESI) 274.0 [M+H]+.
[0132] To a stirred solution of 8-bromo-4-hydroxy-6-methyl-2/Z-pyrano[2,3- c]pyridine-2-thione (2.00 g, 7.38 mmol) in acetone (30 mL) was added K2CO3 (2.03 g, 14.8 mmol). The reaction was stirred at rt for 15 min. To the resulting suspension was added EtI (0.60 mL, 7.4 mmol). The reaction was stirred at rt for 16 h. Upon completion, the reaction mixture was concentrated. The residue was dissolved DCM (25 mL) and washed with water (2 x 25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography to afford 8-bromo-2-(ethylthio)-6-methyl- 4/Z-pyrano[2,3-c]pyridin-4-one (0.6 g, 27%). MS (ESI) 300.1 [M+H]+.
[0133] To a stirred solution of 8-bromo-2-(ethylthio)-6-methyl-4/Z-pyrano[2,3- c]pyridin-4-one (1.8 g, 6.02 mmol) in DCM (38 mL) was added m-CPBA (4.15 g, 24.08 mmol) at 0 °C then stirred at rt for 16 h. Upon completion, the reaction was quenched with water (30 mL) and washed with saturated NaHCCh aqueous and water (30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography to afford 8-bromo-2-(ethylsulfonyl)-6-methyl-4/Z-pyrano[2,3-c]pyridin-4- one (1.3 g, 65%). MS (ESI) 322.5 [M+H]+.
Step 8: Preparation of 8-bromo-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z-pyrano[2,3- c]pyridin-4-one
[0134] To a stirred solution of 8-bromo-2-(ethylsulfonyl)-6-methyl-4/Z- pyrano[2,3-c]pyridin-4-one (1.30 g, 3.92 mmol) and 4,4-difluoropiperidine hydrochloride (1.17 g, 7.85 mmol) in DCM (20 mL) was added DIEA (2.05 mL, 11.8 mmol) at 0 °C. The reaction was stirred at rt for 16 h. Upon completion, the reaction was quenched with water (20 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography to afford 8- bromo-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z-pyrano[2,3-c]pyridin-4-one (1.2 g, 87%). MS (ESI) 351.0 [M+H]+.
Step 9: Preparation of 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z-pyrano[2,3- c]pyridine-4-one
[0135] To a stirred suspension of 8-bromo-2-(4,4-dimethylpiperidin-l-yl)-6- methyl-4/Z-pyrano[2,3-c]pyridin-4-one (0.600 g, 1.71 mmol) in 1,4-dioxane (6 mL) was added tributyl(l -ethoxy vinyl) stannane (0.680 g, 1.71 mmol) and Pd(PPh2)Ch (60 mg, 0.08 mmol). The mixture was purged with N2 then heated at 90 °C for 24 h. After cooling down to rt, to the reaction mixture was added 2N HC1 (10 mL). The reaction was heated at 50 °C for 30 min. The volatiles were evaporated under pressure and the residue was dissolved in DCM (30 mL). The organic layer was washed with saturated Na2COs (30 mL). The organic layer was then washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography to afford 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z- pyrano[2,3-c]pyridine-4-one (500 mg, 93%). MS (ESI) 315.3 [M+H]+.
Step 10: Preparation of N-((R)-l-(2,(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- pyrano[2,3-c]pyridine-8-yl)ethyl)-2-methylpropane-2-sulfinamide
[0136] To a stirred solution of 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-6-methyl- 4/Z-pyrano[2,3-c]pyridine-4-one (0.900 g, 2.86 mmol) and (R)-2-methylpropane-2- sulfinamide (1.30 g, 11.5 mmol) in THF (9 mL) was added Ti(OiPr)4 (6.50 mL, 22.9 mmol). The reaction was refluxed for 24 h. After cooling down to rt, the reaction was quenched with brine (40 mL), then diluted with EtOAc (40 mL). The precipitate was removed by filtration through a celite pad that was washed with EtOAc (3 x 20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (40 mL). The combined organic layers were washed with water (75 mL) and brine (100 mL). The organic layer was then dried (Na2SO4) and filtered, then concentrated. The residue was dissolved in THF (12 mL) and AcOH (1.15 g, 19.2 mmol) and NaCNBHs (0.450 g, 7.19 mmol) were added at -15 °C. The resulting mixture was stirred at rt for 10 h. Upon completion, the reaction was quenched with saturated aqueous Na2COs at 0 °C until pH~ 8-9. The mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine, dried (Na2SO4) and filtered, then concentrated. The residue was purified by flash chromatography to afford N-((R)-l-(2,(4,4- dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-pyrano[2,3-c]pyridine-8-yl)ethyl)-2- methylpropane-2-sulfinamide (0.6 g, 51%). MS (ESI) 420.4 [M+H] +.
Step 11: Preparation of (R)-8-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z- pyrano[2,3-c]pyridin-4-one
[0137] To a stirred solution of N-((R)-l-(2,(4,4-dimethylpiperidin-l-yl)-6-methyl- 4-oxo-4H-pyrano[2,3-c]pyridine-8-yl)ethyl)-2-methylpropane-2-sulfinamide (0.600 g, 1.48 mmol) in 1,4-dioxane (3 mL) was added HC1 (4M in 1,4-dioxane, 6 mL). The reaction was stirred at rt for 3 h. Upon completion, solvent was removed under reduced pressure, the reaction was triturated with diethyl ether (2 x 5 mL). The product was dissolved in water (5 mL), neutralized with sat. NaHCO,, and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to afford (R)-8-(l-aminoethyl)- 2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4/Z-pyrano[2,3-c]pyridin-4-one (0.37 g, 82%). MS (ESI) 316.4 [M+H]+.
Step 12: Preparation of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo- 4/Z-pyrano[2,3-c]pyridin-8-yl)ethylamino)benzoate
[0138] To a stirred solution of (R)-8-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l- yl)-6-methyl-4/Z-pyrano[2,3-c]pyridin-4-one (370 mg, 1.17 mmol) in 1,4-dioxane (3.7 mL) was added methyl 2-bromobenzoate (277 mg, 1.29 mmol) and CS2CO3 (1.08 g, 3.52 mmol). The reaction mixture was degassed with N2 for 15 min. Pd2(dba)3 (107 mg, 0.117 mmol) and XanthPhos (101 mg, 0.176 mmol) were added and the resulting mixture was again degassed with N2 for 15 min. The reaction was heated at 95 °C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite. The volatiles were removed under reduced pressure, and the residue was partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated, and the aqueous layer was further washed with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by Chiral SFC (Lux Cellulose-C4 (30 x 250 mm column), 30% MeOH) to afford methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-pyrano[2,3-c]pyridin- 8-yl)ethyl)amino)benzoate (130 mg, 24%). 99.2% Chiral purity (Chiralpak AS-H (4.6 x 250 mm column) 20% MeOH w/ 0.5% modifier). MS (ESI) 450.8 [M+H]+.
(R)-2-((l-2-(4,4-Dimethylpiperidin-l-yl)-6-methyl-4-oxo-4/Z-pyrano[2,3-c]pyridin-8- yl]ethylamino)benzoic acid
Step 13: Preparation of (R)-2-((l-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4/Z- pyrano [2,3 -c]pyridin- 8-yl] ethylamino )benzoic acid
[0139] To a stirred solution of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6- methyl-4-oxo-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate (130 mg, 0.28 mmol) in MeOH (1.3 mL) was added NaOH (2N, 1.16 mL, 2.31 mmol) at 0 °C. The reaction was stirred at rt for 16 h. Upon completion, the solvent was removed under reduced pressure then mixture was acidified with 2N HC1. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by achiral SFC purification to afford (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo- 4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoic acid (25 mg, 20%), 99.8% Chiral purity (Chiralcel-OD-3 (4.6 x 250 mm column) 20% MeOH). ’H NMR (400 MHz, DMSO-d6) 5 12.66 (br s, 1H), 8.87 (br s, 1H), 7.79 (d, 7=8 Hz, 1H), 7.56 (s, 1H), 7.29 (s, 1H), 6.77 (d, 7=4Hz, 1H), 6.53 (m, 1H), 5.63 (s, 1H), 5.2 (br s, 1H), 3.58 (m, 4H), 2.50 (s, 3H), 1.57-1.42 (m, 7H), 0.98 (s, 6H). MS (ESI) 436.4 [M+H]+.
Example 3
Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-(hydroxymethyl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoic acid
[0140] To a stirred solution of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-formyl- 6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (Example 11) (70.0 mg, 0.152
mmol) in THF (2.1 mL) was added NaBH4 (11.5 mg, 0.303 mmol) at 0 °C. The reaction was stirred for 30 min at rt. The reaction was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase HPLC chromatography (Cl 8, H2O/CH3CN) to afford (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-(hydroxymethyl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid (5 mg, 8%). Chiral purity 96.4% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); XH NMR (400 MHz, DMSO-d6) 5 12.74 (s, 1H), 8.50 (s, 1H), 7.80 (d, 7=8 Hz, 1H), 7.63 (s, 1H), 7.39-7.38 (m, 1H), 7.20 (t, J= 12 MHz, 1H), 6.54-6.51 (t, 7=12.3 Hz, 1H), 6.43 (d, 7=8 Hz, 1H), 5.05 (s, 1H), 4.78 (t, 7=12 Hz, 1H), 4.38-4.31 (m, 2H), 3.69-3.67 (m, 4H), 2.31 (s, 3H), 1.58 (d, 7=4 Hz, 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H); MS (ESI) 463.3 [M-H]“.
Example 4
(R)-2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)-6-methyl-4-oxo-4H-chromen- 8-yl)ethyl)amino)benzoic acid
Step 1: Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
[0141] (R)-2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin- l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following the procedure for Step 3 of Example 6 to afford the title compound (1.7 g, 95%), MS (ESI) 435.4 [M+H]+.
Step 2: Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
[0142] To a stirred solution of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl- 4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (1.70 g, 3.91 mmol) in DMF (8.5 mL) was added K2CO3 (810 mg, 5.87 mmol). The reaction was stirred for 30 min at rt and benzyl bromide (797 mg, 4.30 mmol) was added at 0 °C. The reaction was stirred for 6 h at rt. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/petroleum ether) to afford benzyl (R)-2-((l- (2-(4,4-dimethylpiperidin- l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (1.5 g, 73%). Chiral purity 98.4% (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 525.6 [M+H]+.
Step 3: Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0143] Benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoate was prepared from benzyl (R)-2-((l-(2-(4,4- dimethylpiperidin- l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 10 of Example 11 to afford the title compound (1.2 g, 64%). Chiral purity
99.7% (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 651.2 [M+H]+.
Step 4: Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-3- vinyl-4H-chromen-8-yl)ethyl)amino)benzoate
[0144] Benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-3-vinyl- 4H-chromen-8-yl)ethyl)amino)benzoate was prepared from benzyl (R)-2-((l-(2-(4,4- dimethylpiperidin-l-yl)-3-iodo-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate and tributyl(vinyl)stannane following a procedure for Step 11 of Example 11 to afford the title compound (300 mg, 70%). Chiral purity 99.7% (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 551.6 [M+H]+.
Step 5: Preparation of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)- 6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0145] To a stirred solution of benzyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6- methyl-4-oxo-3-vinyl-4H-chromen-8-yl)ethyl)amino)benzoate (300 mg, 0.545 mmol) in THF (1.5 mL) was added a 0.5 M solution in THF of 9-borabicyclo[3.3.1]nonane (10.9 mL, 5.45 mmol) at 0 °C. The reaction was stirred at rt for 5 h. 2N NaOH (1.5 mL) and 30% H2O2 (1.5 mL) were added at 0 °C and the reaction was stirred at rt for 16 h. The reaction was quenched with saturated NaHCOa (15 mL) and extracted with EtOAc (2 x 15 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/petroleum ether) to afford benzyl (R)-2-((l-(2-(4,4- dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate (200 mg, 64%). MS (ESI) 569.7 [M+H]+.
Example 4
Step 5: Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid
[0146] To a suspension 10% Pd/C (100 mg) in THF (2 mL) was added benzyl (R)- 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate (200 mg, 0.351 mmol). The reaction was stirred under an atmosphere of H2 at rt for 12 h. The reaction was filtered through a celite bed that was washed with DCM (10 mL). The solvent was evaporated. The residue was purified by preparative SFC (Chiralcel-OX-3 (4.6 x 250 mm column) 40% (0.25% DEA in MeOH)) to afford (R)-2-((l-(2- (4,4-dimethylpiperidin-l-yl)-3-(2-hydroxyethyl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid (17 mg, 10%). Chiral purity 97.7% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); ’H NMR (400 MHz, DMSO-d6) 5 12.56 (s, 1H), 8.76 (s, 1H), 7.82 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.14 (s, 1H), 6.51-6.48 (t, 7=12 Hz, 1H), 6.39 (s, 1H), 5.05 (s, 1H), 4.71 (s, 1H), 3.61-3.60 (m, 2H), 3.44-3.42 (m, 4H), 2.60 (t, 7=12 Hz, 2H), 2.29 (s, 3H), 1.57 (d, 7=8 Hz, 3H), 1.48-1.45 (m, 4H), 0.98 (s, 6H); MS (ESI) 479.9 [M+H]+.
Example 5
(R)-2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9- yl)ethyl)amino)-6-fluorobenzoic acid
Step 1: Preparation of methyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[ 1 ,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoate
[0147] Methyl (R)-2-(( 1 -(2-(4,4-dimethylpiperidin- 1 -yl)-7 -methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoate was prepared from (R)-9-(l- aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2-a]pyrimidin-4-one and methyl 2-bromo-6-fluorobenzoate following a procedure for Step 6 of Example 1 to obtain the title compound (100 mg, 27%). Chiral purity 99.8% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 467.5 [M+H] +.
Example 5
Step 2: Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid
[0148] (R)-2-(( 1 -(2-(4,4-Dimethylpiperidin- 1 -yl)-7 -methyl-4-oxo-4H-pyrido[ 1 ,2- a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid was prepared from methyl (R)-2-((l-(2- (4,4-dimethylpiperidin- 1 -yl)-7 -methyl-4-oxo-4H-pyrido[ 1 ,2-a]pyrimidin-9-yl)ethyl)amino)- 6-fluorobenzoate following the procedure for Step 7 of Example 1 to obtain the title compound
(69 mg, 71%). Chiral purity 99.4% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); XH NMR (400 MHz, DMSO-d6) 5 13.15 (bs, 1H), 8.51 (s, 1H), 8.14-8.13 (m, 1H), 7.57 (d, 7=1.6 Hz, 1H), 7.18-7.13 (m, 1H), 6.34 (dd, 7=11.6, 8.4 Hz, 1H), 6.15 (d, 7=8.8 Hz, 1H), 5.62 (s, 1H), 5.19-5.16 (m, 1H), 3.64 (bs, 4H), 2.23 (s, 3H), 1.56-1.54 (d, 7=6.8 Hz, 3H), 1.38-1.35 (m, 4H), 0.97 (s, 6H); MS (ESI) 451.3 [M-H]’.
Example 6
(R)-2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-3-fluoro-7-methyl-4-oxo-4H-pyrido[l,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid
Step 1: Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-
[0149] tert-Butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate was prepared from (R)-9-(l-aminoethyl)- 2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4H-pyrido[l,2-a]pyrimidin-4-one and tert-butyl 2- bromobenzoate following a procedure for the preparation of Step 6 of Example 1 to obtain the title compound (150 mg, 48%). Chiral purity 99.6% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 491.6 [M+H] +.
Step 2: Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-fluoro-7-methyl- 4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
[0150] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)- 7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (300 mg, 0.610 mmol) in DCM (3 mL) was added Selectfluor (1.00 g, 2.80 mmol). The reaction was stirred at 50 °C for 16 h. The reaction was quenched with water (5 mL) and extracted with DCM (2 x 5 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/petroleum ether) to afford tert-butyl (R)-2- ((l-(2-(4,4-dimethylpiperidin-l-yl)-3-fluoro-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (80 mg, 26%). Chiral purity 99.6% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 509.6 [M+H]+.
Step 3: Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-fluoro-7-methyl-4-oxo-
[0151] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)- 3-fluoro-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (80 mg, 0.16 mmol) in DCM (0.4 mL) was added TFA (0.8 mL) at 0 °C. The reaction was stirred at rt for 4 h. The reaction was concentrated under reduced pressure and residue was dissolved in EtOAc (25 mL). The organic layer was washed with sat. NaHCCh (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/petroleum ether) to afford (R)-2-((l-(2-(4,4-dimethylpiperidin- l-yl)-3-fluoro-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (34 mg, 56%). Chiral purity 99.6% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); ’H NMR (400 MHz, DMSO-d6) 5 12.73 (bs, 1H), 8.48 (s, 1H), 8.39-8.37 (m, 1H),
7.80 (d, 7=7.6 Hz, 1H), 7.57 (s, 1H), 7.21 (t, 7=15.6 Hz, 1H), 6.55 (t, 7=12 Hz, 1H), 6.33 (d, 7=12 Hz, 1H), 5.23-5.22 (m, 1H), 3.77-3.74 (m, 4H), 2.25 (s, 3H), 1.58-1.57 (d, 7=4 Hz, 3H), 1.43-1.42 (m, 4H), 0.99 (s, 6H); MS (ESI) 451.3 [M-H]’.
Example 7
(R)-2-(( 1 -(3-Chloro-2-(4,4-dimethylpiperidin- 1 -yl)-7 -methyl-4-oxo-4H-pyrido[ 1 ,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid
Step 1: Preparation of tert-butyl (R)-2-((l-(3-chloro-2-(4,4-dimethylpiperidin-l-yl)-7-methyl- 4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
[0152] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)- 7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 0.306 mmol) in DCM (1.5 mL) was added N-chlorosuccinimide (48.0 mg, 0.367 mmol) at 0 °C. The reaction was stirred at 0 °C to rt for 1 h. The reaction was quenched with water (2 mL) and extracted with DCM (2 x 4 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/Pet. ether) to afford tert-butyl (R)-2-((l-(3-chloro-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 37%). Chiral purity 98.1% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 525.6 [M+H]+.
Step 2: Preparation of (R)-2-((l-(3-chloro-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo- 4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
[0153] (R)-2-((l-(3-Chloro-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l- (3-chloro-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9- yl)ethyl)amino)benzoate following the procedure for Step 3 of Example 6 to obtain the title compound (26 mg, 56 %). Chiral purity 98.1% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); ’H NMR (400 MHz, DMSO-d6) 5 12.73 (bs, 1H), 8.54 (s, 1H), 8.38 (d, 7=4Hz, 1H), 7.80 (dd, 7=1.6, 7=8.0, 1H), 7.65-7.64 (m, 1H), 7.22 (t, 7=8.4 Hz, 1H), 6.55 (t, 7=7.2 Hz, 1H), 6.36 (d, 7=8.4 Hz, 1H), 5.25-5.22 (m, 1H), 3.69-3.67 (m, 4H), 2.27 (s, 3H), 1.60-1.58 (d, 7=8 Hz, 3H), 1.47-1.44 (m, 4H), 0.98 (s, 6H); MS (ESI) 469.6 [M+H]+.
Examples 8 and 9
2-(((R)-l-(2-((R)-3-(lH-Pyrazol-4-yl)piperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid and 2-(((R)-l-(2-((S)-3-(lH-Pyrazol-4-yl)piperidin-l-yl)-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid
Step 1: Preparation of tert-butyl 2-(((R)-l-(2-3-(lH-pyrazol-4-yl)piperidin-l-yl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0154] To a stirred solution of tert-butyl (R)-2-((l-(2-(ethylsulfonyl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate (400 mg, 0.848 mmol) and 3-(lH-pyrazol-4- yl)piperidine dihydrochloride (228 mg, 1.02 mmol) in DCM (4 mL) was added DIPEA (0.444 mL, 2.50 mmol) at 0 °C. The reaction was stirred at rt for 16 h. Water (5 mL) was added to the reaction and the mixture was extracted with DCM (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/Pet. ether) to afford tert-butyl 2-(((R)-l-(2-3-(lH-pyrazol-4- yl)piperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (260 mg, 58%). MS (ESI) 529.7 [M+H]+. The diastereomers were separated by chiral SFC chromatography (Chiralpak AS-H (4.6 x 250 mm column) 40 % MeOH) to give peak 1 (75 mg) and peak 2 (80 mg). Peak 1: Chiral purity 98.7% (Chiralpak AS-H (4.6 x 250 mm column), 40% MeOH); MS (ESI) 529.5 [M+H]+. Peak 2: Chiral purity 99.2% (Chiralpak AS-H (4.6 x 250 mm column), 40% MeOH); MS (ESI) 529.6 [M+H]+.
Step 2: Preparation of 2-(((R)-l-(2-((R)-3-(lH-Pyrazol-4-yl)piperidin-l-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoic acid and 2-(((R)-l-(2-((S)-3-(lH-Pyrazol-4- yl)piperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid
[0155] 2-(((R)- 1 -(2-((R)-3 -( lH-Pyrazol-4-yl)piperidin- 1 -yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid and 2-(((R)-l-(2-((S)-3-(lH-Pyrazol-4-yl)piperidin- l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid were synthesized from the separated peaks 1 and 2 from Step 1 following a procedure for Step 3 of Example 6 to afford the title compounds. From Peak 1: (29 mg, 41%). Chiral purity 99.8% (Chiralpak AS-H (4.6 x 250 mm column), 40% MeOH); ’H NMR (400 MHz, DMSO-d6) 5 12.5 (s, 1H), 8.37 (d, 7=8 Hz, 1H), 7.82-7.80 (d, 7=8.0 Hz, 1H), 7.62-7.61 (m, 1H), 7.52 (s, 2H), 7.37-7.36 (m, 1H), 7.24 (t, 7=15 Hz 1H), 6.54 (t, 7=15 Hz, 1H), 6.45 (d, 7=8 Hz, 1H), 5.64 (s, 1H), 5.07-5.04 (m, 1H), 4.16-4.07 (m, 2H), 3.16-3.06 (m, 2H), 2.88-2.82 (m, 1H), 2.32 (s, 3H), 2.07-2.05 (m, 1H), 1.81-1.79 (m, 1H), 1.69-1.64 (m, 2H),_1.56 (d, 7=7 Hz, 3H); MS (ESI) 472.6 [M+H]+. From
Peak 2: (23 mg, 32%), Chiral purity 99.0% (Chiralpak AS-H (4.6 x 250 mm column), 40% MeOH); ’H NMR (400 MHz, DMSO-d6) 5 12.5 (s, 1H), 8.33 (d, 7=6 Hz, 1H), 7.81-7.79 (d, 7=8.0 Hz, 1H), 7.60-7.61 (m, 1H), 7.55 (s, 2H), 7.35-7.34 (m, 1H), 7.-7.21 (t, 7=7.2 Hz, 1H), 6.57-6.55 (m, 1H), 6.43-6.40 (d, 7=8 Hz, 1H), 5.61 (s, 1H), 5.09-5.04 (m, 1H), .4.02-4.00 (m, 2H), 3.16-3.06 (m, 2H), 2.86-2.80 (m, 1H), 2.29 (s, 3H), 2.07-2.05 (m, 1H), 1.77-1.57 (m, 6H).; MS (ESI) 472.6 [M+H]+. Examples 8 and 9 are diastereomers and the stereochemistry shown for each at C(3) of the piperidine ring has been assigned arbitrarily, and thus may be the opposite of that depicted.
Example 10
(R)-2-((l-(3-Cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid
Step 1: Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-7-methyl-
[0156] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)- 7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (400 mg, 0.816 mmol) in DCM (4 mL) was added N-iodosuccinimide (183 mg, 0.816 mmol) at 0 °C. The reaction was stirred at rt for 1 h. The reaction was quenched with water (5 mL) and extracted with DCM (2 x 5 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/petroleum ether) to afford tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-7-methyl-4-oxo-4H-pyrido[l,2-
a]pyrimidin-9-yl)ethyl)amino)benzoate (450 mg, 89%). Chiral purity 98.0% (Chiralpak AS- H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 617.7 [M+H]+.
Step 2: Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-
[0157] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)- 3-iodo-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (400 mg, 0.649 mmol) in NMP (4 mL) was added CuCN (112 mg, 0.973 mmol) at rt. The reaction was stirred at 130 °C for 1 h in the microwave. Water (10 mL) was added and the mixture was extracted with EtOAc (2 x 15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/Pet. ether) to afford tert-butyl (R)-2-((l-(3-cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (320 mg, 96%). Chiral purity 99.6% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 516.5 [M+H]+.
Example 10
Step 3: Preparation of (R)-2-((l-(3-cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo- 4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
[0158] (R)-2-((l-(3-Cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l- (3-cyano-2-(4,4-dimethylpiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9- yl)ethyl)amino)benzoate following the procedure for step 3 of Example 6 to obtain the title
compound (53 mg, 59 %); Chiral purity 99.6% (Chiralcel OD-3 (4.6 x 250mm column), 30% (0.5% DEA in MeOH)); ’H NMR (400 MHz, DMSO) 5 12.75 (s, 1H), 8.47 (s, 1H), 8.54 (d, 7=6.4 Hz, 1H), 7.81 (dd, 7=8 Hz, 7= 1.6 Hz, 1H), 7.71 (d, 7=2.0 Hz, 1H), 7.22 (t, 7=4 Hz, 1H), 6.56 (t, 7=4 Hz, 1H), 6.35 (d, 7=8.4 Hz, 1H), 5.15-5.10 (m, 1H), 3.94-3.91 (m, 4H), 2.25 (s, 3H), 1.57-1.55 (d, J=6.8 Hz, 3H), 1.47-1.45 (m, 4H), 1.00 (s, 6H); MS (ESI) 458.3 [M-H]’.
Example 11
(R)-2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid
[0159] To a stirred solution of l-(3-bromo-2-hydroxy-5-methylphenyl)ethan-l-one (200 g, 133 mmol) in DMF (800 mL) was added a solution of NBS (236.7 g 133.0 mmol) in DMF (800 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction was quenched with water (2000 mL) and stirred for 30 min. The product was collected by filtration and dissolved in EtOAc (2000 mL). The organic layer was washed with water (2 x IL). The organic layer was then dried (Na2SO4), filtered and evaporated to dryness to afford l-(3- bromo-2-hydroxy-5-methylphenyl)ethan-l-one (250 g, 82%). MS (ESI) m/z 228.9 [M+H]+.
[0160] To a stirred solution of l-(3-bromo-2-hydroxy-5-methylphenyl)ethan-l-one
(250 g, 1.09 mol) in THF (2500 mL) was added 2M NaHMDS in THF (1528 mL, 3056 mmol)
at -78 °C. The reaction was stirred at 0 °C for 2 h. The reaction was cooled to -78 °C and CS2 (66.35 mL, 1.310 mmol) was added. The reaction was stirred for 24 h at rt. The reaction was cooled to -50 °C and 15% H2SO4 (2500 mL) was added drop-wise. The reaction was stirred for 30 min at -50 °C. The layers were separated and the acqueous layer was extracted with EtOAc (1250 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was triturated with DCM (1250 mL). The product was collected and dried under high vacuum to afford 8-bromo-4-hydroxy-6-methyl-2H-chromene- 2-thione (152 g, 64%). MS (ESI) 273.0 [M+H] +.
[0161] To a stirred solution of 8-bromo-4-hydroxy-6-methyl-2H-chromene-2- thione (152 g, 563 mmol) in acetone (1520 mL) was added K2CO3 (93.3 g, 675 mmol). The reaction was stirred at rt for 15 min. Ethyl iodide (159.0 mL, 1978 mmol) was added and the reaction was stirred 60 °C for 16 h. The solvent was evaporated and water (760 mL) was added. The mixture and extracted with DCM (1520 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/petroleum ether) to afford 8-bromo-2-(ethylthio)-6-methyl-4H-chromen-4-one (120.5 g, 72%). MS (ESI) 299.0 [M+H] +.
[0162] To a stirred solution of 8-bromo-2-(ethylthio)-6-methyl-4H-chromen-4-one (19.0 g, 63.5 mmol) in DCM (190 mL) was added m-CPBA (43.84 g, 254.2 mmol) at 0 °C. The reaction was stirred rt for 16 h. The reaction was quenched with water (200 mL). The layers were separated and the organic layer was washed with saturated NaHCCh (3 X 100 mL). The separated organic layer was dried (Na2SO4), filtered and concentrated. The residue was
purified by flash chromatography (SiCL, EtOAc/Pet. ether) to afford 8-bromo-2- (ethylsulfonyl)-6-methyl-4H-chromen-4-one (12 g, 57%). MS (ESI) 331.1 [M+H]+.
[0163] To a stirred solution of 8-bromo-2-(ethylsulfonyl)-6-methyl-4H-chromen-
4-one (10.0 g, 28.6 mmol) and 4,4-dimethylpiperidine hydrochloride (5.42 g, 36.2 mmol) in DCM (100 mL, 10V) was added DIPEA (11.7 g, 90.6 mmol) at 0 °C. The reaction was stirred at rt for 16 h. The reaction was quenched with water (100 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/Pet. ether) to afford 8-bromo-2-(4,4-dimethylpiperidin-l-yl)- 6-methyl-4H-chromen-4-one (7 g, 67%). MS (ESI) 350.1.
[0164] A stirred solution of 8-bromo-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4H- chromen-4-one (15 g, 43 mmol) and tributyl(l -ethoxy vinyl) stannane (17.1 g, 47.3 mmol) in 1,4-dioxane (150 mL) was purged with N2 for 15 min. PdCh(PPh3)2 (1.50 g, 2.14 mmol) was added and the reaction was stirred at 90 °C for 12 h. The reaction was cooled to rt and 2N HC1
(150 mL) was added. The reaction was stirred at 50 °C for 1 h. The reaction was cooled to rt. The mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/petroleum ether) to afford 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4H- chromen-4-one (11.5 g, 83 %). MS (ESI) 314.3 [M+H]+.
Step 7: Preparation of (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)-2-methylpropane-2-sulfinamide
[0165] To a stirred solution of 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-6-methyl- 4H-chromen-4-one (11.5 g, 36.7 mmol) and (R)-2-methylpropane-2-sulfinamide (8.89 g, 73.5 mmol) in THF (115 mL) was added Ti(0Et)4 (50.25 g, 220.4 mmol). The reaction was stirred at 60 °C for 12 h. The reaction was quenched with water (115 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude oil was dissolved THF (180 mL) cooled to -15 °C. AcOH (20.76 mL, 346.2 mmol) and NaCNBHs (8.04 g, 129.8 mmol) were added. The reaction was stirred at -15 °C and allowed to warm to rt over 5 h. The reaction was quenched with saturated NaHCOa (360 mL) and the mixture was extracted with EtOAc (2 x 250 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc/Pet. ether) to afford (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfinamide (10 g, 65%). Chiral purity 87% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 419.5 [M+H]+.
Step 8: Preparation of (R)-8-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4H- chromen-4-one
[0166] To a stirred solution of (R)-N-((R)-l-(2-(4,4-dimethylpiperidin-l-yl)-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfinamide (10.0 g, 29.9 mmol) in 1,4-dioxane (50 mL) was added 4M HC1 in dioxane (100 mL) at 0 °C. The reaction was stirred at rt for 6 h. The reaction was concentrated, and the residue was triturated with diethyl ether (100 mL). The compound was neutralized with saturated NaHCCh (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and
concentrated. The residue was purified by flash chromatography (SiCh, DCM/MeOH) to afford (R)-8-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4H-chromen-4-one (6.5 g, 86%). Chiral purity 89% (Chiralcel OX-3 (4.6 x 250mm column), 30% (0.5% DEA in MeOH)); MS (ESI) 315.5 [M+H]+.
Step 9: Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-
[0167] To a stirred solution of (R)-8-(l-aminoethyl)-2-(4,4-dimethylpiperidin-l- yl)-6-methyl-4H-chromen-4-one (5.80 g, 18.5 mmol) and tert-butyl 2-bromobenzoate (7.11 g, 27.7 mmol) in 1,4-dioxane (58 mL) was added CS2CO3 (18.0 g, 55.4 mmol). The reaction was purged with N2 for 15 min. Pd2(dba)3 (1.68 g, 1.84 mmol) and Xantphos (1.60 g, 2.76 mmol) were added. The reaction was stirred at 95 °C for 16 h. The reaction was quenched with water (60 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/petroleum ether) and chiral SFC chromatography ((Chiralpak-IG (25 x 250 mm), 25% MeOH) to afford tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate (6 g, 66%). Chiral purity 99.7 % (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 491.6 [M+H]+.
Step 10: Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-iodo-6-methyl- 4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0168] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-
6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (1.00 g, 2.04 mmol) in DCM (15
mL) was added N-iodosuccinimide (367 mg, 1.63 mmol) at 0 °C. The reaction was stirred the rt for 5 h. The reaction was quenched with water (10 mL) and extracted with DCM (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/petroleum ether) to afford tert-butyl (R)-2-((l-(2-(4,4- dimethylpiperidin-l-yl)-3-iodo-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (900 mg, 71%). Chiral purity 97.9% (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 617.6 [M+H]+.
Step 11: Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-
[0169] A stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3- iodo-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (1.00 g, 1.93 mmol) and tributyl(vinyl)stannane (2.58 g, 8.12 mmol) in 1,4-dioxane (10 mL) was purged with N2 for 20 min. Pd(PPhs)4 (93.7 mg, 0.081 mmol) was added and the reaction was stirred at 90 °C for 16 h. The reaction was diluted with water (10 ml) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, EtOAc/Pet. ether) to afford tert-butyl (R)-2-((l-(2- (4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-3-vinyl-4H-chromen-8- yl)ethyl)amino)benzoate (700 mg, 83%). Chiral purity 98.4% (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 517.7 [M+H]+.
Step 12: Preparation of tert-butyl 2-(((lR)-l-(3-(l,2-dihydroxyethyl)-2-(4,4- dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0170] To a stirred solution of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)- 6-methyl-4-oxo-3-vinyl-4H-chromen-8-yl)ethyl)amino)benzoate (700 mg, 1.36 mmol) in acetone (7 mL) and water (7 mL) were added potassium osmate dihydrate (25 mg, 0.067 mmol) and 4-methyl morpholine-N-oxide (274 mg, 2.03 mmol). The reaction was stirred at rt for 18 h. The solvent was evaporated and the residue was triturated with DCM (5 mL). The resulting product was collected by filtration and dried under high vacuum to afford tert-butyl 2-(((lR)- l-(3-(l,2-dihydroxyethyl)-2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate (650 mg, 87%). MS (ESI) 551.8 [M+H]+.
Step 13: Preparation of tert-butyl (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-formyl-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0171] To a stirred solution of tert-butyl 2-(((lR)-l-(3-(l,2-dihydroxyethyl)-2- (4,4-dimethylpiperidin- 1 -yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (650 mg, 1.18 mmol) in DCM (5.2 mL) and MeOH (5.2 mL) was added sodium periodate (1.01 g, 4.73 mmol). The reaction was stirred at rt for 28 h. The solvent was evaporated and water (10 mL) was added. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/petroleum ether) to afford tert-butyl (R)-2-((l-(2-(4,4- dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (270 mg, 44%). MS (ESI) 519.7 [M+H]+.
Step 14: Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoic acid
[0172] (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo-
4H-chromen-8 yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l-(2-(4,4- dimethylpiperidin-l-yl)-3-formyl-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following the procedure for Step 3 of Example 6 to obtain the title compound (11 mg, 22%). Chiral purity 97.3% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); ’H NMR (400 MHz, DMSO-d6) 5 12.77 (s, 1H), 9.93 (s, 1H), 8.34-8.32 (m, 1H), 7.81 (d, 7=12 Hz, 1H), 7.68 (d, 7=4 Hz, 1H), 7.43 (d, 7=2.4 Hz, 1H), 7.23 (t, 7=20 Hz, 1H), 6.56 (t, 7=8 Hz, 1H), 6.49 (d, 7=12 Hz, 1H), 5.07-5.04 (m, 1H), 3.62-3.61 (m, 4H), 2.31 (s, 3H), 1.61-1.59 (d, J=8 Hz, 3H), 1.55-1.52 (m, 4H), 1.00 (s, 6H); MS (ESI) 463.6 [M+H]+.
Example 12
(R)-2-((l-(3-Cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid
[0173] 8-Acetyl-2-(ethylthio)-6-methyl-4H-chromen-4-one was prepared from 8- bromo-2-(ethylthio)-6-methyl-4H-chromen-4-one and tributyl(l -ethoxy vinyl)stannane following a procedure for Step 6 of Example 11 to afford the title compound (47 g, 45%). MS (ESI) 263.3 [M+H]+.
Step 2: Preparation of (R)-N-((R)-l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)- 2-methylpropane-2-sulfinamide
[0174] To a stirred solution of 8-acetyl-2-(ethylthio)-6-methyl-4H-chromen-4-one (47.5 g, 181 mmol) and (R)-2-methylpropane-2-sulfinamide (43.94 g, 362.6 mmol) in THF (475 mL) was added Ti(0Et)4 (206.8 g, 906.5 mmol). The reaction was stirred at reflux for 24 h. The reaction was cooled to rt. Water (475 mL) and EtOAc (250 mL) were added with stirring. The mixture was filtered through a celite pad that was rinsed with EtOAc (250 mL). The layers were separated, and the water layer was washed with EtOAc (200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to give an oil. The crude oil was dissolved in THF (500 mL) and cooled to -15 °C. AcOH (63.41 mL, 1.094 mol) and NaCNBHs (42.98 g, 684.0 mmol) were added at -15 °C. The reaction was stirred from - 15 °C to rt over 5 h. The reaction was quenched with saturated NaHCOs (950 mL). The mixture was extracted with EtOAc (950 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated to afford racemic (R)-N-(l-(2-(ethylthio)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfinamide (35 g, 53%). 30 g of the racemic material was purified by chiral SFC (Chiralpak-IG (4.6 x 150 mm column) 15% MeOH) to afford (R)-N-((R)-l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2- methylpropane-2-sulfinamide (12 g, 18%). Chiral purity 99.7% (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 368.4 [M+H]+.
[0175] (R)-8-(l-Aminoethyl)-2-(ethylthio)-6-methyl-4H-chromen-4-one was prepared from (R)-N-((R)- l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2- methylpropane-2-sulfinamide following a procedure for Step 8 of Example 11 to afford the
title compound (7.2 g, 84%). Chiral purity 99.7% (Chiralpak AS-H (4.6 x 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 264.2 [M+H]+.
Step 4: Preparation of tert-butyl (R)-2-((l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate
[0176] tert-Butyl (R)-2-((l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate was prepared from (R)-8-(l-aminoethyl)-2-(ethylthio)-6-methyl-4H- chromen-4-one and tert-butyl 2-bromobenzoate following a procedure for Step 9 of Example 11 to afford the title compound (4.3 g, 48%). Chiral purity 99.7% (Chiralpak IC (4.6 x 250 mm column), 0.5% DEA in MeOH); MS (ESI) 440.5 [M+H]+.
Step 5: Preparation of tert-butyl (R)-2-((l-(2-(ethylsulfonyl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate
[0177] tert-Butyl (R)-2-((l-(2-(ethylsulfonyl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2-(ethylthio)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 4 of Example 11 to afford the title compound (2 g, 55%). MS (ESI) 472.4 [M+H]+.
Step 6: Preparation of tert-butyl (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoate
[0178] tert-Butyl (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2- (ethylsulfonyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate and 4,4- difluoropiperidine hydrochloride following a procedure for Step 5 of Example 11 to afford the title compound (4.3 g, 48%). MS (ESI) 499.6 [M+H]+.
Step 7: Preparation of tert-butyl (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-3-iodo-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0179] tert-Butyl (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-3-iodo-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2-(4,4- difluoropiperidin- l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 10 of Example 11 to afford the title compound (155 mg, 85%). MS (ESI) 625.6 [M+H]+.
Step 8: Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl- 4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0180] tert-Butyl (R)-2-((l-(3-cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2-(4,4-
difluoropiperidin-l-yl)-3-iodo-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 2 of Example 10 to afford the title compound (103 mg, 80%). MS (ESI) 524.2 [M+H]+.
Step 9: Preparation of (R)-2-((l-(3-cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
[0181] (R)-2-((l-(3-Cyano-2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l-(3-cyano-2- (4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 3 of Example 6 to afford the title compound (19 mg, 19%). Chiral purity 99.1% (Chiralcel OD-3 (4.6 x 250mm column), 30% (0.5% DEA in MeOH)); ’H NMR (400 MHz, CDC13) 5 12.78 (s, 1H), 8.34-8.32 (d, 7=5.6 Hz, 1H), 7.81 (dd, 7=8 Hz, 1.6 Hz, 1H), 7.66-7.65 (m, 1H), 7.46-7.45 (m, 1H), 7.23 (t, 7=16 Hz, 1H), 6.57 (t, 7=14Hz, 1H), 6.46 (d, 7=8.4 Hz, 1H), 5.05-5.02 (m, 1H ), 4.01-3.98 (m, 4H), 2.23-2.31 (m, 7H), 1.58 (d, 7=4 Hz, 3H); MS (ESI) 466.3 [M-H]’.
Example 13
Step 1: Preparation of tert-butyl (R)-2-((l-(6-methyl-2-(6-methylpyridin-2-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
[0182] To a stirred solution of tert-butyl (R)-2-((l-(2-(ethylthio)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoate (200 mg, 0.46 mmol) and (6-methylpyridin-2- yl)boronic acid (250 mg, 1.82 mmol) in 1,4-dioxane (4 mL), was added CS2CO3 (592 mg, 1.82 mmol) and copper (I) 3 -methylsalicylate (293 mg, 1.37 mmol). The resulting mixture was purged with N2 for 15 min followed by addition of Pd(PPhs)4 (52.5 mg, 0.045 mmol). The reaction was heated at 90 °C for 24 h. After cooling down to rt, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by Prep HPLC (Acquity UPLC BEH Cl 8, (50 mm x 2.1 mm column), H2O/ACN with 10 mM NH4HCO3 as modifier) to afford tert-butyl (R)-2-((l-(6-methyl-2-(6-methylpyridin-2-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate (60 mg, 28%). MS (ESI) 471.6 [M+H]+.
Step 2: Preparation of (R)-2-((l-(6-Methyl-2-(6-methylpyridin-2-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
[0183] To a stirred solution of tert-butyl (R)-2-((l-(6-methyl-2-(6-methylpyridin- 2-yl)-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (60 mg, 0.13 mmol) in DCM (0.6 mL) was added TFA (0.9 mL) at 0 °C. The reaction was stirred at rt for 12 h. Upon completion, the reaction mixture was concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/Petro. ether) to afford (R)-2-((l-(6-methyl-2-(6-methylpyridin-2-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid (23.7 mg, 44%). ’H NMR (400 MHz, DMSO-d6) 5 12.76 (s, 1H), 8.46 (d, 7=5.6 Hz, 1H), 8.07 (d, 7=7.6 Hz, 1H), 7.94 (t, 7=7.6 Hz, 1H), 7.82 (d, 7=1.2 Hz, 1H), 7.80 (d, 7=1.6 Hz, 1H), 7.58 (d, 7=4 Hz, 1H), 7.50 (d, 7=7.6 Hz 1H), 7.22 (m,
2H), 6.55 (m, 2H), 5.38 (t, 7=6.4 Hz, 1H), 2.60 (s, 3H), 2.37 (s, 3H), 1.69 (d, 7=6.8 Hz, 3H). 99.90 % purity (X Bridge BEH C18 (4.6 x 50 mm column) ACN/H2O with 10 mM NH4HCO3 as modifier). MS (ESI) 413.3 [M-H]’.
Example 14
[0184] Example 14 was prepared similarly to Example 13. ’H NMR (400 MHz, DMSO-d6) 5 12.76 (s, 1H), 8.55 (s, 1H), 8.42 (d, 7=4 Hz, 1H), 8.20 (s, 1H), 7.81 (dd, 7=1.2 Hz, 1H), 7.70 (d, 7=1.2 Hz, 1H), 7.51 (d, 7=2 Hz, 1H), 7.21 - 7.26 (m, 1H), 6.74 (s, 1H), 6.50- 6.57 (m, 2H), 5.33 (m, 1H), 3.93 (s, 3H), 2.34 (s, 3H), 1.63 (d, 7=6.4 Hz, 3H). 99.6 % Chiral purity (Chiralcel-AD-3 (4.6 x 250 mm column) 30% MeOH w/ 0.5% DEA as modifier). MS (ESI) 402.0 [M-H]'.
Example 15
(R)-2-((l-(2-(l,3-Dimethyl-lH-pyrazol-4-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid
[0185] Example 15 was prepared similarly to Example 13. ’H NMR (400 MHz, DMSO-d6) 5 12.78 (s, 1H), 8.47 (s, 1H), 8.41 (d, 7=6 Hz, 1H), 7.82 (dd, 7=8.0, 1.6 Hz, 1H), 7.71-7.70 (m, 1H), 7.48 (d, 7=2 Hz, 1H), 7.24-7.20 (m, 1H), 6.56 (t, 7=8 Hz, 1H), 6.49 (s, 1H), 6.43 (d, 7=8.4 Hz, 1H), 5.31-5.24 (m, 1H), 3.85 (s, 3H), 2.51-2.47 (m, 3H), 2.34 (s, 3H), 1.61
(d, 7=6.4 Hz, 3H). 99.75 % Chiral purity (Chiralpak AS-H (4.6 x 250 mm column) 20% MeOH w/ 0.5% DEA as modifier). MS (ESI) 416.4 [M-H]+.
Example 16
2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid
[0186] To a solution of 2-amino-3-bromo-5-methylbenzoic acid (2.13 g, 9.25 mmol) in DMF (19.99 mL) under N2 at rt was added DIEA (4.93 mL, 27.8 mmol). The reaction mixture was cooled down to 0 °C then T3P (50% in DMF, 4.7 mL, 9.25 mmol) was added followed by 2M methylamine in THF (6.48 mL, 12.95 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCOa (25 mL) aqueous solution then extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, then concentrated to afford 2-amino-3- bromo-N,5-dimethylbenzamide (1.47g, 66%), which was taken to the next step without further purification. 1 H NMR (400 MHz, METHANOL-d4) 5 ppm 7.37 (d, J=2.69 Hz, 1 H), 7.25 (dd, J=1.96, 0.73 Hz, 1 H), 2.86 (s, 3 H), 2.22 (s, 3 H); LCMS 243.0 [M+H] +.
Step 2: Preparation of 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3/f)-one
[0187] Triphosgene (0.400 g, 1.33 mmol) was added into a flask containing 2- amino-3-bromo-N, 5 -dimethylbenzamide (0.81 g, 3.33 mmol) in CH2CI2 (33.3 mL). The reaction was heated under reflux for 19 h. After cooling to rt, the reaction was concentrated under reduced pressure to afford 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3H)-one (0.91 g, 101%), which was taken to the next step without further purification. ’H NMR (400 MHz, METHANOL-d4) 5 ppm 7.88 (s, 1 H), 7.86 - 7.90 (m, 1 H), 7.78 (s, 1 H), 3.39 (s, 3 H), 2.40- 2.38 (m, 3 H), 2.38-2.37 (m, 3 H); LCMS 269.0 [M+H] +.
[0188] A mixture of 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3/f)-one (1.20 g, 4.48 mmol), P(O)Ch (5.11 mL, 53.7 mmol) and DIEA (3.18 mL, 17.90 mmol) were added in a 100 mL round bottom flask then heated at 95 °C overnight. After cooling down to rt, excess P(O)C13 was removed by under pressure. The residue was diluted with CH2CI2 then cooled in an ice bath following by addition of a suspension of NaHCCh aqueous solution (5M, 20 mL). The resulting suspension solution was stirred for 15min; precipitation was filtered under pressure and washed with DCM (2 x 150 mL). The organic layers were washed with water and brine, dried (MgSCL), and filtered, then concentrated to afford 8-bromo-2-chloro- 3,6-dimethylquinazolin-4(3//)-one (1.77 g, 61%) which was taken to the next step without further purification. ’H NMR (400 MHz, DMSO-d6) 5 = 8.02 (s, 1H), 7.91 (s, 1H), 3.32 (s, 3H), 2.44 (s, 3H); LCMS 289.0 [M+H] +.
Step 4: Preparation of 8-bromo-2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethylquinazolin-
[0189] 8-Bromo-2-chloro-3,6-dimethylquinazolin-4(3//)-one (1.77 g, 3.72 mmol), 4,4-dimethylpiperidine (0.550 g, 4.84 mmol) and N,N-diisopropylethylamine (1.99 mL, 11.2 mmol) in DMSO (9.31 mL) was heated at 90 °C overnight. After cooling to rt, the reaction
mixture was quenched with water (10 mL), extracted with DCM (3 x 10 mL), extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, then concentrated. The residue was purified by flash chromatography (SiO2, EtOAc/Hex) to afford 8-bromo-2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethylquinazolin- 4(3H)-one (1.15 g, 85%). ’H NMR (400 MHz, DMSO-76) 5 ppm 7.87 (d, 7=1.59 Hz, 1 H), 7.80 (dd, 7=1.83, 0.86 Hz, 1 H), 3.43 (s, 3 H), 3.18 - 3.26 (m, 4 H), 2.38 (s, 3 H), 1.46 - 1.53 (m, 4 H), 1.00 (s, 6 H); LCMS 365.1 [M+H] +.
Step 5: Preparation of 2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-8-(prop-l-en-2- yl)quinazolin-4(3/f)-one
[0190] A solution of 8-bromo-2-(4,4-dimethylpiperidin-l-yl)-3,6- dimethylquinazolin-4(3/Z)-one (1.15 g, 3.16 mmol), Pd(PPh2)Ch (0.11 g, 0.16 mmol), K2CO3 (1.31 g, 9.49 mmol), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (1.84 mL, 9.49 mmol) in 1,4-dioxane (14.77 mL) and water (6.33 mL) was degassed for 15 min then heated at 50 °C overnight. 1,4-Dioxane was removed under pressure then diluted with ethyl acetate and washed with water and brine. The aqueous layer was back extracted with EtOAc (lx). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/Hex) to afford 2-(4,4-dimethylpiperidin- l-yl)-3,6-dimethyl-8-(prop-l-en-2-yl)quinazolin-4(3/f)-one (1.01 g, 97%). ’H NMR (400 MHz, DMSO-76) 5 ppm 7.77 (dd, 7=2.08, 0.86 Hz, 1 H), 7.40 (d, 7=1.71 Hz, 1 H), 5.13 (dd, 7=2.26, 0.79 Hz, 1 H), 5.11 - 5.21 (m, 1 H), 3.44 (s, 3 H), 3.06 - 3.17 (m, 4 H), 2.38 (s, 3 H), 2.25 (s, 3 H), 1.44 - 1.52 (m, 4 H), 0.99 (s, 6 H). ; LCMS 362.0 [M+H] +.
[0191] To vigorously stirred solution of 2-(4,4-dimethylpiperidin-l-yl)-3,6- dimethyl-8-(prop-l-en-2-yl)quinazolin-4(3//)-one (1.00 g, 3.07 mmol) in CH2CI2 (18.68 mL) and ACN (18.68 mL) were added 2,6-dimethylpyridine (0.71 mL, 6.15 mmol), water (28.0 mL) and NalCL (2.63 g, 12.29 mmol) sequentially. To the resulting mixture a stock solution of ruthenium(III)chloridehydrate (0.03 g, 0.108 mmol) in water (0.035M, 3.0 mL) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water then washed with CH2CI2 (2x). The combined organic layers were washed with brine, dried (MgSCL), filtered, and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc/Hex) to afford 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethylquinazolin- 4(3H)-one (0.57 g, 57%). ’H NMR (400 MHz, DMSO-76) 5 ppm 8.01 (dd, 7=2.26, 0.79 Hz, 1 H), 7.75 - 7.72 (m, 1 H), 3.46 (s, 3 H), 3.24 - 3.15 (m, 4 H), 2.78 (s, 3 H), 2.41 (s, 3 H), 1.53 - 1.46 (m, 4 H), 1.00 (s, 6 H); LCMS 328.2 [M+H] +.
Step 7: Preparation of 2-(4,4-dimethylpiperidin-l-yl)-8-(l -hydroxy ethyl)-3, 6- dimethylquinazolin-4(3//)-one
[0192] To a yellow suspension of 8-acetyl-2-(4,4-dimethylpiperidin-l-yl)-3,6- dimethylquinazolin-4(3/Z)-one (0.22 g, 0.66 mmol) in MeOH (2 mL) under N2 at 0 °C was added NaBH4 (0.04 g, 0.99 mmol). The reaction was stirred at rt overnight. Upon completion, the reaction mixture was quenched with saturated NaHCCh (5 mL) then extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and filtered, then concentrated to afford 2-(4,4-dimethylpiperidin-l-yl)-8-(l -hydroxy ethyl)-3, 6- dimethylquinazolin-4(3/f)-one (0.22g, 100%) which was taken to the next step without further purification. ’H NMR (400 MHz, DMSO-d6) 5 = 7.69 (s, 1H), 7.64 (d, 7=2.1 Hz, 1H), 5.46 -
5.39 (m, 1H), 5.14 (d, 7=4.6 Hz, 1H), 3.44 (s, 3H), 3.23 - 3.07 (m, 4H), 2.39 (s, 3H), 1.54 - 1.44 (m, 4H), 1.37 (d, 7=6.4 Hz, 3H), 0.99 (s, 6H); LCMS 330.2 [M+H]+.
Step 8: Preparation of l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl methanesulfonate
[0193] To a solution of 2-(4,4-dimethylpiperidin-l-yl)-8-(l -hydroxy ethyl)-3, 6- dimethylquinazolin-4(3//)-one (0.23 g, 0.65 mmol) in CH2CI2 (3.24 mL) at 0 °C under N2 was added DIEA (0.250 mL, 1.42 mmol) and Mesyl chloride (0.100 mL, 1.29 mmol). The reaction was stirred for 1 h then quenched with water and extracted with DCM (2x). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford l-(2-(4,4- dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl methanesulfonate (0.27 g, 101%) which was carried on to the next step without further purification.
Step 9: Preparation of methyl 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate
[0194] To a solution of l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl methanesulfonate (0.27 g, 0.66 mmol) in ACN (3.28 mL) was added DIEA (0.59 mL, 3.28 mmol) and methylanthranilate (0.21 mL, 1.64 mmol) under N2. The reaction mixture was heated at 60 °C overnight. Upon completion, ACN was removed by under pressure then quenched with water. The reaction mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2SO4), and filtered then concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/Hex) to afford methyl 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-
yl)ethyl)amino)benzoate (0.22 g, 74%). 1 H NMR (400 MHz, DMSO-d6) 5 = 8.39 (d, 7=7.5 Hz, 1H), 7.78 (dd, 7=8.0, 1.7 Hz, 1H), 7.71 (dd, 7=2.1, 0.9 Hz, 1H), 7.50 (d, 7=2.0 Hz, 1H), 7.24 (ddd, 7=8.5, 7.0, 1.6 Hz, 1H), 6.62 (d, 7=8.4 Hz, 1H), 6.51 (t, 7=7.3 Hz, 1H), 5.36 (t, 7=7.0 Hz, 1H), 3.81 (s, 3H), 3.47 (s, 3H), 3.29 - 3.17 (m, 4H), 2.33 (s, 3H), 1.60 (d, 7=6.7 Hz, 3H), 1.52 (t, 7=5.5 Hz, 4H), 1.02 (s, 6H); LCMS 463.2 [M+H]+.
Step 10: Preparation of 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid
[0195] Lithium hydroxide monohydrate (2N, 0.069 mL, 0.14 mmol) was added into a stirred suspension of methyl 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (0.016 g, 0.035 mmol) in MeOH (1.0 mL) and THF (0.50 mL) at rt. The resulting solution was heated at 60 °C overnight. After cooling down to 0 °C, HC1 (2N, aqueous) was added to adjust the pH to 2. Solvents were removed under pressure then diluted with water and extracted with DCM (2x). The combined organic layers were washed with brine, dried (Na2SO4), and filtered then concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/Hex) to afford 2-((l-(2-(4,4- dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (16.7 mg, 67%). ’H NMR (400 MHz, DMSO-d6) 5 = 12.60 (br s, 1H), 8.43 (s, 1H), 7.77 (dd, 7=7.9, 1.7 Hz, 1H), 7.70 (dd, 7=2.1, 0.9 Hz, 1H), 7.46 (d, 7=2.1 Hz, 1H), 7.18 (ddd, 7=8.5, 7.0, 1.7 Hz, 1H), 6.52 - 6.46 (m, 2H), 5.40 (br s, 1H), 3.32 (s, 3H), 3.23 (br t, 7=5.5 Hz, 4H), 2.32 (s, 3H), 1.60 - 1.46 (m, 7H), 1.00 (s, 6H); LCMS 449.3 [M+H]+.
Example 17
(R)-5-(2-((l-(2-(4,4-Dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one
Step 1: Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzohydrazide
[0196] To a stirred solution of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl- 4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (200 mg, 0.460 mmol) in DMF (2 mL) were added HATU (0.26 g, 0.69 mmol), DIPEA (0.23 mL, 1.4 mmol) at 0 °C. The reaction was stirred for 5 min at 0 °C. Hydrazine hydrate (34 mg, 0.69 mmol) was added and the reaction was stirred at rt for 16 h. The reaction was quenched with water (5 mL) and stirred for 10 min. The mixture was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCL, MeOH/DCM) to afford (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzohydrazide (180 mg, 87%). MS (ESI) 449.5 [M+H]+.
Step 2: Preparation of (R)-5-(2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one
[0197] To a stirred solution of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-6-methyl- 4-oxo-4H-chromen-8-yl)ethyl)amino)benzohydrazide (180 mg, 0.400 mmol) in THF (1.8 mL) was added Et3N (0.12 mL, 0.80 mmol) followed by 1,1 -carbonyldiimidazole (84.6 mg, 0.520 mmol) at 0 °C. The reaction was stirred at rt for 2 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by preparative SFC chromatography (YMC Diol 120 (21 x 210 mm column) 20% MeOH) to afford (R)-5-(2-((l- (2-(4,4-dimethylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)phenyl)- l,3,4-oxadiazol-2(3H)-one (60 mg, 32%). Chiral purity 99.5% (Chiralpak AS-H (4.6 x 250 mm column), 40% (0.2% 7 M NH3 in CH3CN:MeOH, 1:1)); ’H NMR (400 MHz, DMSO-d6) 5 12.50 (bs, 1H), 7.61-7.60 (m, 1H), 7.54 (dd, 7=8.0, 1.2 Hz, 1H), 7.37-7.36 (d, 7=2.0 Hz, 1H), 7.26-7.25 (m, 1H), 7.21 (t, 7=7.2 Hz, 1H), 6.68 (t, 7=7.2 Hz, 1H), 6.52 (d, 7=8.4 Hz, 1H), 5.52 (s, 1H), 5.16-5.12 (m, 1H), 3.55-3.52 (m, 4H), 2.29 (s, 3H), 1.60 (d, 7=6.4 Hz, 3H), 1.41-1.39 (m, 4H), 0.97 (s, 6H); MS (ESI) 475.3 [M+H]+.
Example 18
(R)-5-(2-((l-(2-(4,4-Difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one
Step 1: Preparation of (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
[0198] (R)-2-((l-(2-(4,4-Difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l-(2-(4,4-difluoropiperidin- l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure for Step 3 of Example 6 to afford the title compound (500 g, 70%). Chiral purity 99.7% (Chiralcel OD- 3 (4.6 x 250 mm column), 30 % (0.5% DEA in MeOH); MS (ESI) 443.2 [M+H]+.
Step 2: Preparation of (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzohydrazide
[0199] (R)-2-((l-(2-(4,4-Difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzohydrazide was prepared from (R)-2-((l-(2-(4,4-difluoropiperidin-l-yl)- 6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid following a procedure for Step 1 of Example 17 to afford the title compound (285 mg, 55%). MS (ESI) 457.3[M+H]+.
Step 3: Preparation of (R)-5-(2-((l-(2-(4,4-difluoropiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one
[0200] (R)-5-(2-((l-(2-(4,4-Difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen- 8-yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one was prepared from (R)-2-((l-(2-(4,4- difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzohydrazide following a procedure for Step 2 of Example 17 to afford the title compound (60 mg, 34%). Chiral purity 99.2% (Chiralcel OD-3 (4.6 x 250 mm column), 30% MeOH); ’H NMR (400 MHz, DMSO-76) 5 12.50 (s, 1H), 7.62 (s, 1H), 7.55 -7.53 (dd, J = 7.6, 1.2 Hz, 1H), 7.38 (s, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.67 (s, 1H), 5.18 - 5.15 (t, J = 6.4 Hz, 1H), 3.70 - 3.68 (m, 4H), 2.30 (s, 3H), 2.15 - 2.05 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H). MS (ESI) 481.4 [M-H]“.
Example 19
(S)-5-(2-((l-(2-(4,4-Difluoropiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)phenyl)-l,3,4-oxadiazol-2(3H)-one
[0201] Example 19 was prepared similarly to Example 18. Chiral purity 99.7% (Chiralpak IG-3 (4.6 x 150 mm column), 60% CO2, 40% MeOH with 0.5% DEA); ’H NMR (400 MHz, DMSO-76) 5 12.65 (s, 1H), 7.63 (s, 1H), 7.60-7.55 (m, 1H), 7.39 (s, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.13 (d, 7 = 7.6 Hz, 1H), 6.71 (t, 7 = 7.6 Hz, 1H), 6.57 (d, 7= 8.4 Hz, 1H), 5.68 (s, 1H), 5.20-5.15 (m, 1H), 3.75-3.65 (m, 4H), 2.30 (s, 3H), 2.15-2.05 (m, 4H), 1.61 (d, 7= 6.8 Hz, 3H). MS (ESI) 481.44 [M-H]“.
Example 20
(R)-2-((l-(2-(l,4-Dimethyl-lH-pyrazol-3-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid
[0202] Example 20 was prepared similarly to Example 13. 97.5 % Chiral purity (Chiralpak AS-H (4.6 x 250 mm column) 20% MeOH w/ 0.5% DEA as modifier); ’H NMR (400 MHz, DMSO-76) 5 12.86 (br s, 1H), 8.51 (br s, 1H), 7.82 (dd, 7=8.0, 1.6 Hz, 1H), 7.74 (s, 2H), 7.50 (d, 7=2.0 Hz, 1H), 7.38 (d, 7=1.6 Hz, 1H), 7.20-7.16 (m, 1H), 6.72 (s, 1H), 6.54 (t, 7=7.2 Hz, 1H), 5.24-5.22 (m, 1H), 3.91 (s, 3H), 2.40 (s, 3H), 2.34 (s, 3H), 1.61 (d, 7=6.4 Hz, 3H); MS (ESI) 416.4 [M-H]“.
Example 21
[0203] Example 21 was prepared similarly to Example 13. 99.5 % Chiral purity (Chiralpak AS-H (4.6 x 250 mm column) 20% MeOH w/ 0.5% DEA as modifier); ’H NMR (400 MHz, DMSO-76) 5 12.77 (br s, 1H), 8.45 (br s, 1H), 7.95 (d, 7=2.0 Hz, 1H), 7.81 (dd, 7=7.6, 1.2 Hz, 1H), 7.73 (d, 7=1.2 Hz, 1H), 7.55 (d, 7=1.2 Hz, 1H), 7.24-7.20 (m, 1H), 7.01 (d, 7=2.0 Hz, 1H), 6.78 (s, 1H), 6.56-6.51 (m, 2H), 5.28 (t, 7=6.4 Hz, 1H), 3.99 (s, 3H), 2.35 (s, 3H), 1.65 (d, 7=6.4 Hz, 3H); MS (ESI) 402.3 [M-H]’.
Example 22
[0204] Example 22 was prepared similarly to Example 13. 99.8 % Chiral purity (Lux Cellulose-2 (4.6 x 250 mm column) 30% MeOH w/ 0.5% DEA as modifier); ’H NMR (400 MHz, DMSO-76) 5 12.75 (br s, 1H), 8.44 (d, 7=6.4 Hz, 1H), 7.95 (t, 7=7.6 Hz, 1H), 7.87 (d, 7=7.2 Hz, 1H), 7.81 (dd, 7=8.0, 1.6 Hz, 1H,), 7.76 (d, 7=1.2 Hz, 1H), 7.58 (d, 7=2 Hz, 1H), 7.25-7.20 (m, 2H), 7.07 (d, 7 = 8 Hz, 1H), 6.55 (t, 7=7.6 Hz, 2H), 5.39-5.33 (m, 1H), 4.00 (s,
3H), 2.37 (s, 3H), 1.69 (d, 7=6.8 Hz, 3H); MS (ESI) 429.3 [M-H]’.
Example 23
(R)-2-((l-(2-(4-Cyano-4-methylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid
Step 1: Preparation of tert-butyl (R)-2-((l-(2-(4-cyano-4-methylpiperidin-l-yl)-6-methyl-4- oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0205] tert-Butyl (R)-2-((l-(2-(4-cyano-4-methylpiperidin-l-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoate was prepared from tert-butyl (R)-2-((l-(2- (ethylsulfonyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate and 4- methylpiperidine-4-carbonitrile hydrochloride following a procedure similar to that used for Step 5 of Example 11 to afford the title compound (0.270 g, 68%). MS (ESI) 502.6 [M+H]+.
Step 2: Preparation of (R)-2-((l-(2-(4-cyano-4-methylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid
[0206] (R)-2-((l-(2-(4-cyano-4-methylpiperidin-l-yl)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoic acid was prepared from tert-butyl (R)-2-((l-(2-(4-cyano- 4-methylpiperidin-l-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate following a procedure similar to that used for Step 3 of Example 6 to afford the title compound (50 mg, 21%). Chiral purity 99.6% (Chiralpak AS-H (4.6 x 250mm column), 20% (0.5% DEA in MeOH)); XH NMR (400 MHz, DMSO- 6) 5 12.76 (br s, 1H), 8.44 (br s, 1H), 7.81 (dd, 7=7.67, 1.2 Hz, 1H), 7.61 (d, 7=1.2 Hz, 1H), 7.38 (d, 7=1.6 Hz, 1H), 7.23 (t, 7=7.2 Hz, 1H), 6.55 (t, 7=7.2 Hz, 1H), 6.45 (d, 7=8.4 Hz, 1H), 5.61 (s, 1H), 5.08 (t, 7=5.2 Hz, 1H), 4.15-4.10 (m, 2H), 3.18 (t, 7=12.0 Hz, 2H), 2.30 (s, 3H), 2.00-1.95 (m, 2H), 1.73-1.65 (m, 2H), 1.64 (d, 7=4.0 Hz, 3H), 1.48 (s, 3H); MS (ESI) 444.3 [M-H]’.
Example 24
(R)-2-((l-(2-(4,4-Difluoropiperidin-l-yl)-7-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid
[0207] Example 24 was prepared similarly to Example 1. 99.8 % Chiral purity (Chiralpak IG (4.6 x 250 mm column) 40% MeOH w/ 0.5% DEA as modifier); 1 H NMR (400 MHz, DMSO-76) 5 12.72 (br s, 1H), 8.56 (s, 1H), 8.40 (d, 7=6.4 Hz, 1H), 7.80 (d, 7=7.60 Hz, 1H) 7.62 (s, 1H), 7.25-7.21 (m, 1H), 6.55 (t, 7=7.2 Hz, 1H), 6.39 (d, 7=8.4 Hz, 1H), 5.80 (s, 1H), 5.24 (t, 7=6.4 Hz, 1H), 3.83-3.82 (m, 4H), 2.25 (s, 3H), 2.08-2.00 (m, 4H), 1.58 (d, 7=6.4 Hz, 3H); MS (ESI) 441.4 [M-H]“.
Example 25
(R)-2-(( 1 -(3-Cy ano-2-(4,4-difluoropiperidin- 1 -yl)-7 -methyl-4-oxo-4H-pyrido[ 1 ,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid
[0208] Example 25 was prepared similarly to Example 10. 99.8 % Chiral purity (Chiralpak IG (4.6 x 250 mm column) 40% MeOH w/ 0.2% DEA as modifier); 1 H NMR (400 MHz, DMSO-76) 5 12.76 (br s, 1H), 8.55 (s, 1H), 8.40 (br s, 1H), 7.82-7.79 (m, 2H), 7.24-7.20 (m, 1H), 6.57 (t, 7=7.2 Hz, 1H), 6.36 (d, 7=8.4 Hz, 1H), 5.18 (t, 7=12.4 Hz, 1H), 4.03 (t, 7=5.2 Hz, 4H), 2.28 (s, 3H), 2.19-2.12 (m, 4H), 1.57 (d, 7=6.4 Hz, 3H); MS (ESI) 468.5 [M+H]+.
Example 26
(R)-2-((l-(3-Cyano-2-(l,4-dimethyl-lH-pyrazol-3-yl)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid
Step 1: Preparation of tert-butyl (R)-2-((l-(2-(ethylthio)-3-iodo-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
[0209] N-iodosuccinimide (0.635 g, 2.82 mmol) was added as a solid to tert-butyl (R)-2-((l-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (1.24 g, 2.82 mmol) in 6 mL 1,2-DCE at 0 °C. The ice bath was removed and the reaction was stirred
for 12 h at rt. 100 mg of N-iodosuccinimide was added and the reaction was stirred at rt for 1 h. The reaction was diluted with DCM (15 mL) and washed with 10% Na2S20s (20 mL), saturated NaHCCh (20 mL) and brine (20 mL). The solution was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiCh, EtOAc/Hex) to afford tert-butyl (R)-2-((l-(2-(ethylthio)-3-iodo-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate (1.5 g, 94%). MS (ESI) 566.1 [M+H]+.
Step 2: Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(ethylthio)-6-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)benzoate
[0210] Copper cyanide (0.238 g, 2.65 mmol) was added to a mixture of tert-butyl (R)-2-((l-(2-(ethylthio)-3-iodo-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (0.500 g, 0.884 mmol) and diisopropylethylamine (0.770 mL, 4.42 mmol) in NMP (1.0 mL). The reaction was stirred for 16 h at 105 °C. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL). The water layer was washed with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc/Hex) to afford tert-butyl (R)-2-((l-(3-cyano-2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoate (0.298 g, 73%). MS (ESI) 465.2 [M+H]+.
Step 3: Preparation of tert-butyl (R)-2-((l-(3-cyano-2-(l,4-dimethyl-lH-pyrazol-3-yl)-6- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate
[0211] tert-Butyl (R)-2-((l-(3-cyano-2-(ethylthio)-6-methyl-4-oxo-4H-chromen- 8-yl)ethyl)amino)benzoate (0.288 g, 0.620 mmol), CS2CO3 (0.404 g, 1.24 mmol) and (1,4-
dimethyl- lH-pyrazol-3-yl)boronic acid (0.174 g, 1.24 mmol) were suspended 1,4-dioxane (2 mL). The suspension was purged with N2 for 10 min. Copper thiophene-2-carboxylate (0.249 g, 1.24 mmol) and tetrakis(triphenylphosphine)palladium (0.072 g, 0.062 mmol) were added. The suspension was purged with N2 for 10 min with stirring. The reaction was stirred at 90 °C for 24 h. The reaction was diluted with EtOAc (10 mL) and filtered through Celite. The Celite pad was rinsed with EtOAc (2 x 10 mL). The solvent was removed and the residue was purified by flash chromatography (SiO2, EtOAc/Hex) to afford tert-butyl (R)-2-((l-(3-cyano-2-(l,4- dimethyl-lH-pyrazol-3-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (0.132 g, 43%). MS (ESI) 499.2 [M+H]+.
Step 4: Preparation of (R)-2-((l-(3-cyano-2-(l,4-dimethyl-lH-pyrazol-3-yl)-6-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)benzoic acid formic acid salt
[0212] To a solution of tert-butyl (R)-2-((l-(3-cyano-2-(l,4-dimethyl-lH-pyrazol- 3-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate (0.125 g, 0.251 mmol) in DCM 1 mL at 0 °C was added TFA (1 mL). The ice bath was removed and the reaction was stirred for 5 h at rt. The solvent was removed and the crude residue was purified by reverse phase HPLC (Water, CH3CN, 0.1 % formic acid) to afford (R)-2-((l-(3-cyano-2-(l,4-dimethyl-lH- pyrazol-3-yl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid formic acid salt (60 mgs, 49%). 1 H NMR (DMSO-d6, 400 MHz) 5 13.47 (br s, 1H), 8.99 (br d, 7=5.9 Hz, 1H), 8.14 (d, 7=2.0 Hz, 1H), 7.79-7.80 (m, 1H), 7.74 (s, 1H), 7.56 (dd, 7=8.8, 2.0 Hz, 1H), 7.50 (d, 7=2.1 Hz, 1H), 6.71 (s, 1H), 6.54 (d, 7=9.0 Hz, 1H), 5.29 (quin, 7=6.3 Hz, 1H), 3.91 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 1.65 (d, 7=6.6 Hz, 3H); MS (ESI) 443.2 [M+H]+.
Examples 27 and 28
(S)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid and (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4- oxo-3, 4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid
Step 1: Preparation of methyl 2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate
[0213] The diastereomers, prepared in Example 16 Step 9, were separated by chiral SFC chromatography (Chiralcel OD-H (30 x 250 mm column), 70% CO2%, 30% ACN) to give Peak 1 (85 mg, 51%) and peak 2 (65 mg, 39%). Peak 1: Chiral purity 96.8% (Chiralpak IC-3 (4.6 x 250 mm column), 70% CO2, 30% (0.5% DEA in MeOH)); MS (ESI) 463.6 [M+H]+. Peak 2: Chiral purity 98.1% (Chiralpak IC-3 (4.6 x 250 mm column), 70% CO2, 30% (0.5% DEA in MeOH)); MS (ESI) 463.6 [M+H]+.
Step 2: Preparation of (S)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid
[0214] (S)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid were synthesized from the separated peak 1 from Step 1 to afford the title compound. To a stirred solution of Peak 1 (95 mg, 0.21 mmol)
in MeOH (0.95 mL) was added 2N NaOH (0.62 mL, 1.23 mmol) at 0 °C. The resulting mixture was stirred at 40 °C for 5 h. After completion, the reaction mixture was concentrated under reduced pressure. Ice-cold water (5 mL) was added and the mixture was acidified with 2N HC1 (until pH = ~6). The precipitated solid was filtered, dried under vacuum and then purified by achiral SFC to afford (S)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4- oxo-3, 4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (22 mg, 24%). Chiral purity 99.8% (Chiralpak IJ-3 (30 x 250 mm column), 70% CO2, 30% MeOH). Specific Optical Rotation [a]D25 °C (C = 0.1% in MeOH) +280.60. ’H NMR (400 MHz, DMSO-d6) 5 12.55 (br s, 1H), 9.19 (br s, 1H), 7.77 (d, 7=7.2 Hz, 1H), 7.68 (s, 1H), 7.46 (d, 7=1.6 Hz, 1H), 7.00 (t, 7=7.2 Hz, 1H), 6.39 (t, 7=7.4 Hz, 1H), 6.32 (d, 7=8.0 Hz, 1H), 5.38 (d, 7=5.6 Hz, 1H), 3.47 (s, 3H), 3.23 (br. s, 4H), 2.30 (s. 3H), 1.54-1.50 (m, 4H), 1.00 (s, 6H). MS (ESI) 447.4 [M-H]“.
Preparation of (R)-2-((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid
[0215] To a stirred solution of Peak 2 (70 mg, 0.15 mmol) in MeOH (0.7 mL) was added NaOH (2N, 0.45 mL, 0.91 mmol) at 0 °C. The resulting mixture was stirred at 50 °C for 5 h. After completion, the reaction mixture was concentrated under reduced pressure. Ice- cold water (1 mL) was added and the mixture was acidified with 2N HC1 (pH = ~6). The precipitate was collected by filtration and triturated in n-pentane (2 x 5 mL) to afford (R)-2- ((l-(2-(4,4-dimethylpiperidin-l-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (36 mg, 53%). Chiral purity 97.5% (Chiralpak IG-3 (4.6 x 150 mm column), 80% CO2, 20% MeOH (0.5% DEA in MeOH). Specific Optical Rotation [a]D25 °C (C = 0.1% in MeOH) -389.28. ’H NMR (400 MHz, DMSO-d6) 5 12.36 (br s, 1H), 9.13 (br s, 1H), 7.73 (dd, 7=1.2, 7.8 Hz, 1H), 7.68 (d, 7=0.8 Hz), 7.46 (d, 7=1.6 Hz, 1H), 7.01 (t, 7=7.2 Hz, 1H), 6.40 (t, 7=7.4 Hz, 1H), 6.34 (d, 7=8.0 Hz, 1H), 5.38 (d, 7=6.4 Hz, 1H), 3.47 (s, 3H), 3.23 (br s, 4H), 2.30 (s, 3H), 1.53-1.51 (m, 4H), 1.01 (s, 6H). MS (ESI) 447.4 [M-H]“.
Examples 29-39
[0216] The compounds of Examples 29-39 are prepared using procedures similar to those described for Examples 1-28, including selection of appropriate starting materials that may be readily obtained from commercial sources, prepared by known and/or published procedures, or provided as otherwise described herein. Structures, IUPAC names and selected analytical data for compounds are summarized in Table B.
Example A
[0217] ADP-Glo assay was used to measure inhibition of lipid kinase activity of PI3Ka (pl l0a/p85a) and PI3K (pl l0a(H1047R)/p85a) with ligands. The kinase reactions utilized ATP and produced ADP as a byproduct. The ADP production was quantified by ADP- Glo luminescence detection. The kinase reaction with lipid substrate PI(4,5)P2:PS (10 pM) was carried out in the presence of ATP (10 pM), the reaction was quenched and remaining ATP was depleted with ADP-Glo™ reagent. ADP was converted to ATP which was measured using a luciferase/luciferin reaction. The substrate (PI(4,5)P2:PS) was prepared in fresh reaction buffer. The kinase was delivered into the substrate solution and gently mixed. The compounds were delivered in 100% DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), and incubated for 20 min at room temperature. ATP was delivered into the reaction mixture to initiate the reaction and the mixture was incubated
for 60 min at 30 °C. The reaction was quenched with ADP-Glo reagent and incubated for 40 min. Detection mixture was added and the mixture incubated for 30 min. Luminescence was measured and converted into pM ADP production based on ADP standard curves. The nonlinear regression to obtain the standard curve and IC50 values were performed using Graphpad Prism software. A large ratio between the wild-type (WT) (PI3Ka (pl 10a/p85a) and H1047R mutant (PI3K (pl l0a(H1047R)/p85a) IC50 indicates compounds that are active in H1047R assay and less active in the wild type. Activity in the WT may result in toxicities, such as hyperglycemia, hyperinsulinemia, gastrointestinal toxicity and rash, thus compounds that preferentially inhibit H104R mutant are beneficial because they reduce toxicities.
[0218] Compound Toxicity was evaluated in in T47D cells using a Cell Titer-Gio (CTG) Assay. The T47D cells were cultured in RPMI1640 medium with 10% FBS and 1% penicillin/streptomycin. The culture medium was removed, the cells were treated with 0.25% trypsin and cell number counted with Vi-CELL XR Cell Viability Analyzer. The cells were plated (3000 cells/100 uL) on 96-well plate and incubated overnight. The cells were treated with compounds at various concentrations in DMSO and incubated for 5 days. The plates were removed from the incubator and let to cool to rt over 30 min. To each well was added 100 uL of CellTiter-Glo reagent (Promega, Cat. No. G7571) and the luminescence was read after 20 min with EnVision Multilabel Reader. The inhibition rates were calculated as: inhibition% = (ZPE-X)/(ZPE-HPE)*100% and XL Fit software was used to calculate IC50 values.
[0219] The results are shown in Table 2 and demonstrate compounds of Formula (I) that are inhibitors of PI3Ka H1047R.
[0220] A is <250 nM
B is >250 nM and < 500 nM
C is >500 nM and < 1000 nM
D is > 1000 nM and < 5,000
E is > 5000 nM and <10,000 nM
F is > 10,000 nM
N/A: Not available
[0221] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure.
Claims
X is C or N;
Y1 is CH, O, S, N, NH or NCH3;
Y2 is C or N;
Z1 and Z2 are independently CH or N; each - independently represents a single bond or a double bond, with the proviso that all chemical valencies are satisfied;
W is C, CH, or N;
Ring A is an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted cycloalkyl, or an unsubstituted or a substituted bicyclic heteroaryl, wherein when the foregoing Ring A is substituted, it is substituted with one or more of -F, -Cl, -CN, -OH, an unsubstituted Ci-6 alkyl, an unsubstituted Ci-6 alkoxy or an unsubstituted Ci-6 haloalkyl;
R1 is H, Ci-C6 alkyl or Ci-Ce alkenyl;
R2 is unsubstituted or a substituted Ci-Ce alkyl or unsubstituted or a substituted Ci-C6 alkenyl, wherein when the foregoing R2 is substituted, it is substituted with one or more of -OH, -F, -CN, -CO(NH2), -COOH, -CH2OH, -CH3, -CF3, or -CF2; or
R1 and R2 together with W form an optionally substituted 4-, 5-, 6-, or 7- membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl,
wherein when the foregoing is substituted, it is substituted with one or more of a monocyclic heteroaryl, -OH, -F, -CN, -CO(NH2), -COOH, -CH2OH, -CH3, -CF3, - CF2, oraCi-Ce alkyl;
R3 is H, -CN, -CHO, -CH=CH2, -CH2CN, -CH(CH3)CN, -C(CH3)2CN, a C1-C4 alkyl, -CH2OH, -CH2NH2, -CH2CH2OH, -CH2CH2NH2, or -CHCONH2;
R4 is H, -F, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OH, or -OCH3;
R5 is H, -CH3, -CH2CH3, -CF2, -CF3, or -CONH2; and
R6 is -COOH, -CN, -CONH2, oxadiazolone, -B(OH)2, -PONH2, -PO(CH3)2, -CONHCH3, -CONHCH2CF3, or -CONHCH2CHF2.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y1 is CH or N.
5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y1 is NH or NCH3.
6. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y1 is O or S.
7. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y1 is O.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y2 is C.
9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y2 is N.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Z1 is CH.
11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Z1 is N.
12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Z2 is CH.
13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Z2 is N.
14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein W is C.
15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein W is CH.
16. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein W is N.
17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted or a substituted aryl.
18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted or a substituted monocyclic heteroaryl.
19. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted or a substituted cycloalkyl.
20. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring A is an unsubstituted or a substituted bicyclic heteroaryl.
21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1 is H.
22. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1 is Ci-Ce alkyl.
23. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1 is Ci-Ce alkenyl.
24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R2 is unsubstituted or a substituted Ci-Ce alkyl.
25. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R2 is unsubstituted or a substituted Ci-Ce alkenyl.
26. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 together with W form an optionally substituted 4-, 5-, 6-, or 7- membered heterocycle.
27. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 together with W form an optionally substituted 5- or 6- membered heteroaryl.
28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
29. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R3 is -CN, -CHO, -CH=CH2, -CH2CN, -CH(CH3)CN, -C(CH3)2CN, or a C1-C4 alkyl.
30. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R3 is -CH2OH, -CH2NH2, -CH2CH2OH, -CH2CH2NH2, or-CHCONH2.
31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R4 is H, -F, -CN, or -CH3.
32. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R4 is -CH2CH3, -CH(CH3)2, -OH, or -OCH3.
33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R5 is H, -CH3, or -CH2CH3.
34. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R5 is -CF2, -CF3, or -CONH2.
35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R6 is -CN, oxadiazolone, -B(OH)2, -PONH2, -PO(CH3)2, -CONHCH3, -CONHCH2CF3, or -CONHCH2CHF2.
36. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R6 is -COOH or -CONH2.
38. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is listed in Table A or Table B herein.
39. A pharmaceutical composition comprising a compound of any one of claims 1 to 38, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
40. A method for treating a cancer or a tumor comprising administering an effective amount of a compound of any one of claims 1 to 38, or a pharmaceutically active salt thereof, or a pharmaceutical composition of claim 39, to a subject having the cancer or the tumor.
41. The method of claim 40, wherein the cancer or the tumor is selected from breast cancer, brain cancer, prostate cancer, head and neck cancer, endometrial cancer, gastric cancer, lymphoma, ovarian cancer, lung cancer, colorectal cancer, non-small cell lung cancer, glioma, bladder cancer, soft tissue sarcoma, esophagogastric cancer, salivary gland cancer, thyroid cancer, hepatobiliary cancer, renal cell carcinoma, melanoma, pancreatic cancer, cervical cancer, and small bowel cancer.
42. Use of an effective amount of a compound of any one of claims 1 to 38, or a pharmaceutically active salt thereof, or a pharmaceutical composition of claim 39, in the manufacture of a medicament for treating a cancer or a tumor.
43. The use of claim 42, wherein the cancer or the tumor is selected from wherein the cancer or the tumor is selected from breast cancer, brain cancer, prostate cancer, head and neck cancer, endometrial cancer, gastric cancer, lymphoma, ovarian cancer, lung cancer, colorectal cancer, non-small cell lung cancer, glioma, bladder cancer, soft tissue sarcoma, esophagogastric cancer, salivary gland cancer, thyroid cancer, hepatobiliary cancer, renal cell carcinoma, melanoma, pancreatic cancer, cervical cancer, and small bowel cancer.
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